Autotaxin inhibitor compounds

ABSTRACT

Described herein are compounds that are autotaxin inhibitors, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders associated with autotaxin activity.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 61/907,965 entitled “AUTOTAXIN INHIBITOR COMPOUNDS”filed on Nov. 22, 2013, and U.S. Provisional Patent Application No.62/038,121 entitled “AUTOTAXIN INHIBITOR COMPOUNDS” filed on Aug. 15,2014, each of which are herein incorporated by reference in theirentirety.

FIELD OF THE INVENTION

Described herein are compounds that are autotaxin inhibitors, methods ofmaking such compounds, pharmaceutical compositions and medicamentscomprising such compounds, and methods of using such compounds in thetreatment of conditions, diseases, or disorders associated withautotaxin activity.

BACKGROUND OF THE INVENTION

Lysophosphatidic acid (LPA) is a lipid mediator that functions, forexample, as a mitogen, chemoattractant, and survival factor for manycell types. LPA signaling is implicated in, for example, cancer andfibrotic diseases.

SUMMARY OF THE INVENTION

Compounds described herein are autotaxin (ATX) inhibitors. In someembodiments, the autotaxin inhibitors described herein are useful asagents for the treatment or prevention of diseases or conditions inwhich ATX and/or LPA participates, is involved in the etiology orpathology of the disease, or is otherwise associated with at least onesymptom of the disease. Inhibition of the physiological activity of ATXand/or LPA is useful in a variety of diseases or conditions. The ATX-LPAsignaling pathway has been implicated in fibrotic diseases and cancer.

Compounds described herein are used in the treatment of diseases orconditions in which autotaxin activity contributes to the symptomologyor progression of the disease, disorder or condition. In one aspect, themethods, compounds, pharmaceutical compositions, and medicamentsdescribed herein comprise autotaxin inhibitors.

In one aspect, described herein is a compound of Formula (I), or apharmaceutically acceptable salt, or solvate thereof:

-   -   wherein,    -   R¹ is —F, —Cl, —Br, —CN, vinyl, C₃-C₆cyloalkyl, —NH₂, —NH(C₁-C₄        alkyl), —N(C₁-C₄ alkyl)₂, —O—C₁-C₄ alkyl, or —S—C₁-C₄ alkyl;    -   R² is H, halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R⁹,        —S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —NR¹⁰S(═O)₂R⁹, —C(═O)R⁹, —OC(═O)R⁹,        —CO₂R¹⁰, —OCO₂R⁹, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —OC(═O)N(R¹⁰)₂,        —NHC(═O)R⁹, —NHC(═O)OR⁹, C₁-C₄alkyl, C₁-C₄fluoroalkyl,        C₁-C₄deuteroalkyl, C₁-C₄hydroxyalkyl, C₁-C₄heteroalkyl,        C₃-C₆cycloalkyl, substituted or unsubstituted phenyl, or        substituted or unsubstituted monocyclic heteroaryl;    -   Ring A is a monocyclic aryl, bicyclic aryl, monocyclic        heterocycloalkyl, monocyclic heteroaryl or bicyclic heteroaryl;        -   each R^(A) is H, halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹,            —S(═O)R⁹, —S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —NR¹⁰S(═O)₂R⁹,            —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —OCO₂R⁹, —N(R¹⁰)₂,            —C(═O)N(R¹⁰)₂, —OC(═O)N(R¹⁰)₂, —NHC(═O)R⁹, —NHC(═O)OR⁹,            C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl,            C₁-C₆heteroalkyl, substituted or unsubstituted            C₃-C₁₀cycloalkyl, substituted or unsubstituted            C₂-C₁₀heterocycloalkyl, substituted or unsubstituted phenyl,            or substituted or unsubstituted monocyclic heteroaryl;        -   m is 0, 1, or 2;    -   L¹ is absent, C₁-C₆alkylene, C₁-C₆fluoroalkylene, or        C₃-C₆cycloalkylene;    -   Q is —CO₂H, —CO₂(C₁-C₆alkyl), —OH, —CN, —B(OH)₂, —C(═O)NHSO₂R⁹,        —C(═O)N(R¹⁰)₂, —SO₂NHC(═O)R⁹, —CN, tetrazolyl, —OP(═O)(OH)₂,        —P(═O)(OH)₂ or carboxylic acid bioisostere;    -   L² is absent, C₁-C₄alkylene, or C₃-C₇cycloalkylene;    -   L³ is —S—, S(═O), S(═O)₂, or —O—;    -   Ring B is a monocyclic aryl, bicyclic aryl, monocyclic        heteroaryl or bicyclic heteroaryl;        -   each R^(B) is independently H, halogen, —CN, —NO₂, —OH,            —OR⁹, —SR⁹, —S(═O)R⁹, —S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂,            —NR¹⁰S(═O)₂R⁹, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —OCO₂R⁹,            —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —OC(═O)N(R¹⁰)₂, —NHC(═O)R⁹,            —NHC(═O)OR⁹, C₁-C₆alkyl, C₁-C₆fluoroalkyl,            C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, substituted or            unsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstituted            C₂-C₁₀heterocycloalkyl, substituted or unsubstituted phenyl,            C₁-C₄alkylene-(substituted or unsubstituted phenyl),            substituted unsubstituted monocyclic heteroaryl,            C₁-C₄alkylene-(substituted or unsubstituted monocyclic            heteroaryl), a substituted or unsubstituted bicyclic            heteroaryl, or C₁-C₄alkylene-(substituted or unsubstituted            bicyclic heteroaryl);        -   n is 0, 1, or 2;    -   R⁹ is C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl,        C₃-C₆cycloalkyl, a substituted or unsubstituted phenyl, a        substituted or unsubstituted monocyclic heteroaryl, or a        substituted or unsubstituted bicyclic heteroaryl;    -   each R¹⁰ is independently selected from H, C₁-C₆alkyl,        C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl, C₃-C₆cycloalkyl, a        substituted or unsubstituted phenyl, or a substituted or        unsubstituted monocyclic heteroaryl; or    -   two R¹⁰ groups attached to the same N atom are taken together        with the N atom to which they are attached to form a substituted        or unsubstituted heterocycle.

For any and all of the embodiments, substituents are selected from amonga subset of the listed alternatives. For example, in some embodiments, Xis —O—, —S—, —S(═O)—, or —S(═O)₂—. In other embodiments, X is —O— or—S—. In other embodiments, X is —S—, —S(═O)—, or —S(═O)₂—. In someembodiments, X is —S—.

In some embodiments, R¹ is —F, —Cl, —Br, —CN, vinyl, cyclopropyl,cyclobutyl, —NH₂, —NH(CH₃), —N(CH₃)₂, —O—CH₃, or —S—CH₃.

In some embodiments, R¹ is vinyl, cyclopropyl, or cyclobutyl.

In some embodiments, R¹ is cyclopropyl, or cyclobutyl.

In some embodiments, R¹ is —F, —Cl, or —Br.

In some embodiments, L² is absent, or C₁-C₄alkylene; L³ is —S—, S(═O),or S(═O)₂.

In some embodiments, L² is absent, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, or—CH(CH₃)—.

In some embodiments, L¹ is absent, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—,—CH(CH₃)—, —CH(CH₂CH₃)—, —C(CH₃)₂—, —C(CH₂CH₃)₂—, cyclopropyl-1,1-diyl,cyclobutyl-1,1-diyl, cyclopentyl-1,1-diyl or cyclohexyl-1,1-diyl; Q is—CO₂H, —CO₂(C₁-C₆alkyl), —C(═O)NHSO₂R⁹ or tetrazolyl.

In some embodiments, L¹ is absent or —CH₂—; Q is —CO₂H, or—CO₂(C₁-C₆alkyl).

In some embodiments, the compound of Formula (I) has the followingstructure of Formula (II):

or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, Ring A is phenyl, naphthyl, monocyclic heteroarylcontaining 1-4 N atoms and 0 or 1 O or S atoms, monocyclic heteroarylcontaining 0-4 N atoms and 1 O or S atoms, bicyclic heteroarylcontaining 1-4 N atoms and 0 or 1 O or S atoms, or bicyclic heteroarylcontaining 0-4 N atoms and 1 O or S atoms; Ring B is phenyl, naphthyl,monocyclic heteroaryl containing 1-4 N atoms and 0 or 1 O or S atoms,monocyclic heteroaryl containing 0-4 N atoms and 1 O or S atoms,bicyclic heteroaryl containing 1-4 N atoms and 0 or 1 O or S atoms, orbicyclic heteroaryl containing 0-4 N atoms and 1 O or S atoms.

In some embodiments, Ring A is phenyl, naphthyl, furanyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, indolyl,indazolyl, benzoxazolyl, benzisoxazolyl, benzofuranyl, benzothienyl,benzothiazolyl, benzimidazolyl, purinyl, cinnolinyl, phthalazinyl,pteridinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, or azaindolyl.

In some embodiments, Ring A is phenyl or naphthyl.

In some embodiments, Ring A is furanyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, or triazinyl.

In some embodiments, Ring A is pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, or triazinyl.

In some embodiments, Ring A is furanyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, or thiadiazolyl.

In some embodiments, Ring A is quinolinyl, isoquinolinyl, quinazolinyl,quinoxalinyl, naphthyridinyl, indolyl, indazolyl, benzoxazolyl,benzisoxazolyl, benzofuranyl, benzothienyl, benzothiazolyl,benzimidazolyl, purinyl, cinnolinyl, phthalazinyl, pteridinyl,pyridopyrimidinyl, pyrazolopyrimidinyl, or azaindolyl.

In some embodiments, each R^(A) is H, halogen, —CN, —OH, —OR⁹, —SR⁹,C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl.

In some embodiments, L³ is —S—.

In some embodiments, L² is absent.

In some embodiments, the compound of Formula (I) or Formula (II) has thefollowing structure of Formula (III):

wherein,

W is CH, CF or N;

or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, L¹ is absent; and Q is —CO₂H.

In some embodiments, described herein is a compound of Formula (III), ora pharmaceutically acceptable salt, or solvate thereof:

-   -   wherein,    -   R¹ is —Cl, —Br, —CN, or C₃-C₆cyloalkyl;    -   R² is H, halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R⁹,        —S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, C₁-C₄alkyl, C₁-C₄fluoroalkyl,        C₁-C₄deuteroalkyl, or C₃-C₆cycloalkyl;    -   R³ is H, halogen, —CN, —OH, C₁-C₄fluoroalkyl, C₁-C₄deuteroalkyl,        C₁-C₄alkoxy, or C₁-C₄fluoroalkoxy;    -   W is CH, CF or N;    -   each R^(A) is H, halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R⁹,        —S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, C₁-C₆alkyl, or C₁-C₆fluoroalkyl;    -   L¹ is absent, C₁-C₆alkylene, or C₃-C₆cycloalkylene;    -   Q is —CO₂H, —CO₂(C₁-C₆alkyl), —OH, —CN, —B(OH)₂, —C(═O)NHSO₂R⁹,        —C(═O)N(R¹⁰)₂, —SO₂NHC(═O)R⁹, —CN, tetrazolyl, —OP(═O)(OH)₂,        —P(═O)(OH)₂ or carboxylic acid bioisostere;    -   Ring B is a monocyclic heteroaryl;        -   each R^(B) is independently H, halogen, —CN, —NO₂, —OH,            —OR⁹, —SR⁹, —S(═O)R⁹, —S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂,            C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl,            substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted            or unsubstituted C₂-C₁₀heterocycloalkyl, substituted or            unsubstituted phenyl, C₁-C₄alkylene-(substituted or            unsubstituted phenyl), substituted unsubstituted monocyclic            heteroaryl, C₁-C₄alkylene-(substituted or unsubstituted            monocyclic heteroaryl), a substituted or unsubstituted            bicyclic heteroaryl, or C₁-C₄alkylene-(substituted or            unsubstituted bicyclic heteroaryl);        -   n is 0, 1, or 2;    -   R⁹ is C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl,        C₃-C₆cycloalkyl, a substituted or unsubstituted phenyl, a        substituted or unsubstituted monocyclic heteroaryl, or a        substituted or unsubstituted bicyclic heteroaryl;    -   each R¹⁰ is independently H, C₁-C₆alkyl, C₁-C₆fluoroalkyl,        C₁-C₆deuteroalkyl, C₃-C₆cycloalkyl, a substituted or        unsubstituted phenyl, or a substituted or unsubstituted        monocyclic heteroaryl; or    -   two R¹⁰ groups attached to the same N atom are taken together        with the N atom to which they are attached to form a substituted        or unsubstituted heterocycle.

In some embodiments, R¹ is —Cl, —Br, —CN, or cyclopropyl. In someembodiments, R¹ is cyclopropyl. In some embodiments, R¹ is —Cl.

In some embodiments, L¹ is absent, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—,—CH(CH₃)—, —CH(CH₂CH₃)—, —C(CH₃)₂—, —C(CH₂CH₃)₂—, cyclopropyl-1,1-diyl,cyclobutyl-1,1-diyl, cyclopentyl-1,1-diyl or cyclohexyl-1,1-diyl; and Qis —CO₂H, —CO₂(C₁-C₆alkyl), —C(═O)NHSO₂R⁹ or tetrazolyl.

In some embodiments, L¹ is absent, —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, orcyclopropyl-1,1-diyl; and Q is —CO₂H, or —CO₂(C₁-C₆alkyl).

In some embodiments, L¹ is absent or —CH₂—; and Q is —CO₂H, or—CO₂(C₁-C₆alkyl).

In some embodiments, Ring B is monocyclic heteroaryl containing 1-4 Natoms and 0 or 1 O or S atoms, or monocyclic heteroaryl containing 0-4 Natoms and 1 O or S atoms.

In some embodiments, Ring B is furanyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, or triazinyl.

In some embodiments, each R^(A) is H, halogen, —CN, —OH, —OR⁹, —SR⁹,C₁-C₆alkyl, or C₁-C₆fluoroalkyl.

In some embodiments, L¹ is absent, —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, orcyclopropyl-1,1-diyl; and Q is —CO₂H.

In some embodiments, L¹ is absent; and Q is —CO₂H.

In some embodiments, the compound or Formula (III) has the followingstructure:

or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, R² is H, F, Cl, Br, I, —CN, —OH, —CH₃, —CF₃, —CD₃,—OCH₃, —OCH₂CH₃, —OCF₃, or —OCH₂CF₃; R³ is H, F, Cl, Br, I, —CN, —OH,—CH₃, —CF₃, —CD₃, —OCH₃, —OCH₂CH₃, —OCF₃, or —OCH₂CF₃.

In some embodiments, R² is Cl; R³ is H, F, or Cl.

In some embodiments, Ring B is furanyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, or triazinyl.

In some embodiments, Ring B is pyrazolyl.

In some embodiments, the compound of Formula (III) has the followingstructure:

or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, R^(A) is H, halogen, —CN, —OH, —OR⁹, —SR⁹,C₁-C₆alkyl, or C₁-C₆fluoroalkyl;

R^(B) is H, C₁-C₆alkyl, C₁-C₆fluoroalkyl, or C₁-C₆deuteroalkyl; R¹ is—Cl, —Br, —CN, or cyclopropyl; R² is H, halogen, —CN, —OH, C₁-C₄alkyl,C₁-C₄fluoroalkyl, C₁-C₄deuteroalkyl, C₁-C₄alkoxy, or C₁-C₄fluoroalkoxy;and R³ is H, halogen, —CN, —OH, C₁-C₄alkyl, C₁-C₄fluoroalkyl,C₁-C₄deuteroalkyl, C₁-C₄alkoxy, or C₁-C₄fluoroalkoxy.

In some embodiments, R¹ is —Cl, or —Br. In some embodiments, R¹ iscyclopropyl.

In some embodiments, the compound of Formula (III) has the followingstructure:

or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, the compound of Formula (III) has the followingstructure:

or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, R^(A) is H, F, Cl, Br, I, —CN, —OH, —OCH₃,—OCH₂CH₃, —OCH₂CF₃, —CH₃, —CH₂CH₃, —CF₃, or —CD₃.

In some embodiments, R^(B) is C₁-C₆alkyl.

In some embodiments, R² is H, F, Cl, Br, I, —CN, —OH, —CH₃, —CF₃, —CD₃,—OCH₃, —OCH₂CH₃, —OCF₃, or —OCH₂CF₃; R³ is H, F, Cl, Br, I, —CN, —OH,—CH₃, —CF₃, —CD₃, —OCH₃, —OCH₂CH₃, —OCF₃, or —OCH₂CF₃.

In some embodiments, R² is Cl; R³ is H, F, or Cl.

In some embodiments, L¹ is absent, —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, orcyclopropyl-1,1-diyl.

In some embodiments, L¹ is absent.

In some embodiments, the compound of Formula (I), Formula (II), orFormula (III) has the following structure of Formula (IV):

wherein,

W is CH, CF or N;

or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, R² is H, halogen, —CN, —OH, C₁-C₄alkyl,C₁-C₄fluoroalkyl, C₁-C₄deuteroalkyl, C₁-C₄alkoxy, C₁-C₄fluoroalkoxy, orC₁-C₄hydroxyalkyl.

In some embodiments, R² is H, F, Cl, Br, I, —CN, —OH, —CH₃, —CF₃, —CD₃,—OCH₃, —OCH₂CH₃, —OCF₃, —OCH₂CF₃, or —CH₂OH.

In some embodiments, R² is Cl.

In some embodiments, R³ is H, halogen, —CN, —OH, C₁-C₄alkyl,C₁-C₄fluoroalkyl, C₁-C₄deuteroalkyl, C₁-C₄alkoxy, C₁-C₄fluoroalkoxy, orC₁-C₄hydroxyalkyl.

In some embodiments, R³ is H, F, Cl, Br, I, —CN, —OH, —CH₃, —CF₃, —CD₃,—OCH₃, —OCH₂CH₃, —OCF₃, —OCH₂CF₃, or —CH₂OH.

In some embodiments, R³ is H, F, or Cl.

In some embodiments, Ring B is phenyl, naphthyl, furanyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, indolyl,indazolyl, benzoxazolyl, benzisoxazolyl, benzofuranyl, benzothienyl,benzothiazolyl, benzimidazolyl, purinyl, cinnolinyl, phthalazinyl,pteridinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, or azaindolyl.

In some embodiments, Ring B is phenyl or naphthyl.

In some embodiments, Ring B is furanyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, or triazinyl.

In some embodiments, Ring B is furanyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, or thiadiazolyl.

In some embodiments, Ring B is pyrazolyl.

In some embodiments, Ring B is pyrazolyl; and each R^(B) isindependently H, C₁-C₆alkyl, C₁-C₆fluoroalkyl, or C₁-C₆deuteroalkyl; nis 1.

In some embodiments, Ring B is pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, or triazinyl.

In some embodiments, Ring B is quinolinyl, isoquinolinyl, quinazolinyl,quinoxalinyl, naphthyridinyl, indolyl, indazolyl, benzoxazolyl,benzisoxazolyl, benzofuranyl, benzothienyl, benzothiazolyl,benzimidazolyl, purinyl, cinnolinyl, phthalazinyl, pteridinyl,pyridopyrimidinyl, pyrazolopyrimidinyl, or azaindolyl.

In some embodiments, the compound of Formula (I) has the followingstructure of Formula (V):

wherein,

W is CH, CF or N;

or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, R^(A) is H, halogen, —CN, —OH, —OR⁹, —SR⁹,C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl; R^(B)is H, C₁-C₆alkyl, C₁-C₆fluoroalkyl, or C₁-C₆deuteroalkyl; R¹ is —F, —Cl,—Br, —CN, C₃-C₆cyloalkyl, —NH₂, or —O—C₁-C₄ alkyl; R² is H, halogen,—CN, —OH, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄deuteroalkyl, C₁-C₄alkoxy,C₁-C₄fluoroalkoxy, or C₁-C₄hydroxyalkyl; R³ is H, halogen, —CN, —OH,C₁-C₄fluoroalkyl, C₁-C₄deuteroalkyl, C₁-C₄alkoxy, C₁-C₄fluoroalkoxy, orC₁-C₄hydroxyalkyl.

In some embodiments, R¹ is —F, —Cl, —Br, —CN, cyclopropyl, —NH₂, or—O—CH₃. In some embodiments, R¹ is —F, —Cl, or —Br. In some embodiments,R¹ is C₃-C₆cyloalkyl. In some embodiments, R¹ is cyclopropyl.

In some embodiments, the compound of Formula (I) or Formula (V) has thefollowing structure of Formula (VI):

wherein,

W is CH, CF or N;

or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, R^(A) is H, F, Cl, Br, I, —CN, —OH, —OCH₃,—OCH₂CH₃, —OCF₃, —OCH₂CF₃, —CH₃, —CH₂CH₃, —CF₃, or —CD₃. In someembodiments, R^(A) is H.

In some embodiments, R^(B) is C₁-C₆alkyl. In some embodiments, R^(B) is—CH₃, —CH₂CH₃, or —CH₂CH₂CH₃, or —CH(CH₃)₂.

In some embodiments, R² is H, F, Cl, Br, I, —CN, —OH, —CH₃, —CF₃, —CD₃,—OCH₃, —OCH₂CH₃, —OCF₃, —OCH₂CF₃, or —CH₂OH. In some embodiments, R² isCl.

In some embodiments, R³ is H, F, Cl, Br, I, —CN, —OH, —CH₃, —CF₃, —CD₃,—OCH₃, —OCH₂CH₃, —OCF₃, —OCH₂CF₃, or —CH₂OH. In some embodiments, R³ isH, F, or Cl.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt, or solvate there, is:

-   3-((2,6-dichloro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (Compound no. 1-1);-   3-((6-chloro-2-cyano-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (Compound no. 1-3);-   3-((6-chloro-2-cyclopropyl-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (Compound no. 1-4);-   3-((2,6-dichloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (Compound no. 1-7);-   3-((2-bromo-6-chloro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (Compound no. 1-2);-   3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (Compound no. 1-10);-   3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (Compound no. 1-16);-   3-((2,6-dichloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (Compound no. 1-13);-   3-((6-Chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (Compound no. 1-34);-   6-((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)picolinic    acid (Compound no. 1-92);-   3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (Compound no. 1-119);-   3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (Compound no. 1-120);-   3-((1-(1-(2-(carbamoyloxy)ethyl)-1H-pyrazol-4-yl)-6-chloro-2-cyclopropyl-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (Compound no. 1-121);-   3-((1-(1-(2-aminoethyl)-1H-pyrazol-4-yl)-6-chloro-2-cyclopropyl-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (Compound no. 1-122);-   3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-(2-ureidoethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (Compound no. 1-123);-   3-((1-(1-(3-carboxypropyl)-1H-pyrazol-4-yl)-6-chloro-2-cyclopropyl-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (Compound no. 1-124);-   3-((1-(1-(4-amino-4-oxobutyl)-1H-pyrazol-4-yl)-6-chloro-2-cyclopropyl-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (Compound no. 1-125);-   3-((2,6-dichloro-7-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (Compound no. 1-49);-   3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (Compound no. 1-126);-   3-((6-chloro-2-cyclopropyl-1-(1-(ethyl-d₅)-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (Compound no. 1-127);-   3-((2,6-dichloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (Compound no. 1-31);-   3-((2,6-dichloro-7-fluoro-1-(pyridin-3-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (Compound no. 2-1);-   3-((2-bromo-6-chloro-7-fluoro-1-(pyridin-3-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (Compound no. 2-2);-   3-((6-chloro-2-cyclopropyl-7-fluoro-1-(pyridin-3-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (Compound no. 2-3);-   3-((1-(1-(6-aminoethyl)-1H-pyrazol-4-yl)-6-chloro-2-cyclopropyl-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (Compound no. 1-128);-   3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-(hex-5-yn-1-yl)-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (Compound no. 1-129);-   3-((1-(1-(3-hydroxy-2,2-dimethylpropyl)-1H-pyrazol-4-yl)-6-chloro-2-cyclopropyl-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (Compound no. 1-130); or-   3-((6-chloro-2-cyclopropyl-1-(1-(6-(3-(3′,6′-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9′-xanthen]-5-yl)ureido)hexyl)-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (Compound 1-131).

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof are chosen by one skilled in the field to providestable moieties and compounds.

In one aspect, described herein is a pharmaceutical compositioncomprising a compound described herein, or a pharmaceutically acceptablesalt, or solvate thereof, and at least one pharmaceutically acceptableexcipient. In some embodiments, the pharmaceutical composition isformulated for administration to a mammal by intravenous administration,subcutaneous administration, oral administration, inhalation, nasaladministration, dermal administration, or ophthalmic administration. Insome embodiments, the pharmaceutical composition is in the form of atablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion,a solution, an emulsion, an ointment, or a lotion.

In one aspect, described herein is a method of treating or preventingany one of the diseases or conditions described herein comprisingadministering a therapeutically effective amount of a compound describedherein, or a pharmaceutically acceptable salt, or solvate thereof, to amammal in need thereof.

In another aspect, described herein is a method for treating orpreventing cancer, or fibrosis, or combinations thereof in a mammalcomprising administering a therapeutically effective amount of acompound described herein, or a pharmaceutically acceptable salt, orsolvate thereof, to the mammal in need thereof.

In one aspect, described herein is a method for treating or preventingcancer in a mammal comprising administering a therapeutically effectiveamount of a compound described herein, or a pharmaceutically acceptablesalt, or solvate thereof, to the mammal in need thereof. In someembodiments, the cancer is amenable to treatment with an autotaxininhibitor. In some embodiments, the method further comprisesadministering a second therapeutic agent to the mammal in addition tothe compound described herein, or a pharmaceutically acceptable salt, orsolvate thereof.

In one aspect, described herein is a method for the treatment orprevention of fibrosis in a mammal comprising administering atherapeutically effective amount of a compound described herein, or apharmaceutically acceptable salt, or solvate thereof, to the mammal inneed thereof. In other embodiments, the fibrosis is amenable totreatment with an autotaxin inhibitor. In some embodiments, the methodfurther comprises administering a second therapeutic agent to the mammalin addition to the compound described herein, or a pharmaceuticallyacceptable salt, or solvate thereof

In any of the aforementioned aspects are further embodiments in whichthe effective amount of the compound described herein, or apharmaceutically acceptable salt thereof, is: (a) systemicallyadministered to the mammal; and/or (b) administered orally to themammal; and/or (c) intravenously administered to the mammal; and/or (d)administered by inhalation; and/or (e) t administered by nasaladministration; or and/or (f) administered by injection to the mammal;and/or (g) administered topically to the mammal; and/or (h) administeredby ophthalmic administration; and/or (i) administered rectally to themammal; and/or (j) adminstered non-systemically or locally to themammal.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound,including further embodiments in which the compound is administered oncea day to the mammal or the compound is administered to the mammalmultiple times over the span of one day. In some embodiments, thecompound is administered on a continuous dosing schedule. In someembodiments, the compound is administered on a continuous daily dosingschedule.

In any of the aforementioned aspects involving the treatment of ATXdependent diseases or conditions are further embodiments comprisingadministering at least one additional agent in addition to theadministration of a compound described herein, or a pharmaceuticallyacceptable salt thereof. In various embodiments, each agent isadministered in any order, including simultaneously.

In any of the embodiments disclosed herein, the mammal is a human.

In some embodiments, compounds provided herein are administered to ahuman.

In some embodiments, compounds provided herein are orally administered.

Articles of manufacture, which include packaging material, a compounddescribed herein, or a pharmaceutically acceptable salt thereof, withinthe packaging material, and a label that indicates that the compound orcomposition, or pharmaceutically acceptable salt, tautomers,pharmaceutically acceptable N-oxide, pharmaceutically active metabolite,pharmaceutically acceptable prodrug, or pharmaceutically acceptablesolvate thereof, is used for inhibiting the activity of autotaxin, orfor the treatment, prevention or amelioration of one or more symptoms ofa disease or condition that would benefit from inhibition of theactivity of autotaxin, are provided.

Other objects, features and advantages of the compounds, methods andcompositions described herein will become apparent from the followingdetailed description. It should be understood, however, that thedetailed description and the specific examples, while indicatingspecific embodiments, are given by way of illustration only, sincevarious changes and modifications within the spirit and scope of theinstant disclosure will become apparent to those skilled in the art fromthis detailed description.

DETAILED DESCRIPTION OF THE INVENTION Autotaxin and LPA

Autotaxin (ATX, NPP2, or E-NPP2), an approximately 120 kDa glycoprotein,is a secreted nucleotide pyrophosphatase/phosphodiesterase (NPP) withlysophospholipase D activity that converts extracellularlysophosphatidylcholine (LPC) and other lysophospholipids tolysophosphatidic acid (LPA). ATX is considered to be responsible for themajority of circulating LPA production.

LPA acts through sets of specific G protein-coupled receptors (GPCRs),such as LPA1, LPA2, LPA3, LPA4, LPA5, LPA6, LPA7, LPA8, in an autocrineand paracrine fashion to produce a variety of biological responses. Forexample, lysophospholipids, such as lysophosphatidic acid (LPA), areknown to affect such biological functions as cellular proliferation,differentiation, survival, migration, adhesion, invasion, andmorphogenesis. In addition, LPA is known to play a role in suchprocesses as platelet activation, smooth muscle contraction, actinstress fiber formation, and cell migration.

ATX and LPA have been detected in various biological fluids such asserum, plasma, cerebrospinal fluid, seminal fluid, urine, and saliva,both in animals and humans, suggesting that they are potentialbiomarkers to predict certain diseases. For example, serum ATXconcentration and activity is elevated in patients with chronic liverdiseases and in pregnant women. In addition, ATX concentration has beenfound to be lower in postoperative cancer patients as a result ofpostoperative damage or poor nutritional state. In addition, ATX isknown to be essential for normal development. For example, ATX-deficientmice die at embryonic day 9.5 with profound vascular defects in both theyolk sac and the embryo. Furthermore, at embryonic day 8.5 ATX-deficientembryos were found to have malformed allantois, neural tube defects, andasymmetric headfolds.

Cancer

ATX has been demonstrated to increase cell motility, neovascularization,proliferation and aggressiveness of tumors. It is upregulated innumerous tumor lineages, such as breast, renal, liver, glioblastoma,ovarian and prostate cancer.

In some embodiments, disclosed herein are methods of treating cancerwith a compound disclosed herein.

ATX is a prometastatic enzyme initially isolated from the conditionedmedium of human melanoma cells. In addition, ATX overexpression isfrequently observed in malignant tumor tissues such as breast cancer,renal cancer, Hodgkin lymphoma, hepatocellular carcinoma, pancreaticcancer and glioblastoma. LPA also contributes to tumorigenesis byincreasing motility and invasiveness of cells.

The term “cancer” as used herein, refers to an abnormal growth of cellsthat tend to proliferate in an uncontrolled way and, in some cases, tometastasize (spread). Types of cancer include, but are not limited to,solid tumors (such as those of the bladder, bowel, brain, breast,endometrium, heart, kidney, lung, liver, uterus, lymphatic tissue(lymphoma), ovary, pancreas or other endocrine organ (thyroid),prostate, skin (melanoma or basal cell cancer) or hematological tumors(such as the leukemias and lymphomas) at any stage of the disease withor without metastases.

Fibrosis

In some embodiments, disclosed herein are methods of treating fibrosiswith a compound disclosed herein.

“Fibrosis,” as used herein, refers to the accumulation of extracellularmatrix constituents that occurs following trauma, inflammation, tissuerepair, immunological reactions, cellular hyperplasia, and neoplasia.

In some embodiments, disclosed herein is a method of reducing fibrosisin a tissue comprising contacting a fibrotic cell or tissue with acompound disclosed herein, in an amount sufficient to decrease orinhibit the fibrosis. In some embodiments, the fibrosis includes afibrotic condition.

In some embodiments, reducing fibrosis, or treatment of a fibroticcondition, includes reducing or inhibiting one or more of: formation ordeposition of extracellular matrix proteins; the number of pro-fibroticcell types (e.g., fibroblast or immune cell numbers); cellular collagenor hydroxyproline content within a fibrotic lesion; expression oractivity of a fibrogenic protein; or reducing fibrosis associated withan inflammatory response.

In some embodiments, the fibrotic condition is primary fibrosis. In someembodiments, the fibrotic condition is idiopathic. In some embodiments,the fibrotic condition is associated with (e.g., is secondary to) adisease; a toxin; an insult (e.g., an environmental hazard); a medicaltreatment, or a combination thereof.

In some embodiments, the fibrotic condition is a fibrotic condition ofthe lung (pulmonary fibrosis), a fibrotic condition of the liver (renalfibrosis), a fibrotic condition of the heart or vasculature (cardiacfibrosis), a fibrotic condition of the kidney (renal fibrosis), afibrotic condition of the skin, a fibrotic condition of thegastrointestinal tract, or a combination thereof.

In some embodiments, the fibrotic condition is a fibrotic condition ofthe lung. In some embodiments, the fibrotic condition of the lung ischosen from one or more of: pulmonary fibrosis, idiopathic pulmonaryfibrosis (IPF), usual interstitial pneumonitis (UIP), interstitial lungdisease, cryptogenic fibrosing alveolitis (CFA), bronchiolitisobliterans, or bronchiectasis. In some embodiments, the fibroticcondition of the lung treated with the methods of the invention isassociated with (e.g., secondary to) a cancer treatment.

In some embodiments, the fibrotic condition is a fibrotic condition ofthe liver.

In some embodiments, the fibrotic condition is a fibrotic condition ofthe heart.

In some embodiments, the fibrotic condition is a fibrotic condition ofthe kidney.

In some embodiments, the fibrotic condition is a fibrotic condition ofthe skin.

In some embodiments, the fibrotic condition is a fibrotic condition ofthe gastrointestinal tract.

Compounds

Compounds described herein, including pharmaceutically acceptable salts,prodrugs, active metabolites and pharmaceutically acceptable solvatesthereof, are autotaxin inhibitors.

In one aspect, described herein is a compound of Formula (I), or apharmaceutically acceptable salt, or solvate thereof:

-   -   wherein,    -   R¹ is —F, —Cl, —Br, —CN, vinyl, C₃-C₆cyloalkyl, —NH₂, —NH(C₁-C₄        alkyl), —N(C₁-C₄ alkyl)₂, —O—C₁-C₄ alkyl, or —S—C₁-C₄ alkyl;    -   R² is H, halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R⁹,        —S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —NR¹⁰S(═O)₂R⁹, —C(═O)R⁹, —OC(═O)R⁹,        —CO₂R¹⁰, —OCO₂R⁹, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —OC(═O)N(R¹⁰)₂,        —NHC(═O)R⁹, —NHC(═O)OR⁹, C₁-C₄alkyl, C₁-C₄fluoroalkyl,        C₁-C₄deuteroalkyl, C₁-C₄hydroxyalkyl, C₁-C₄heteroalkyl,        C₃-C₆cycloalkyl, substituted or unsubstituted phenyl, or        substituted or unsubstituted monocyclic heteroaryl;    -   Ring A is a monocyclic aryl, bicyclic aryl, monocyclic        heterocycloalkyl, monocyclic heteroaryl or bicyclic heteroaryl;        -   each R^(A) is H, halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹,            —S(═O)R⁹, —S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —NR¹⁰S(═O)₂R⁹,            —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —OCO₂R⁹, —N(R¹⁰)₂,            —C(═O)N(R¹⁰)₂, —OC(═O)N(R¹⁰)₂, —NHC(═O)R⁹, —NHC(═O)OR⁹,            C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl,            C₁-C₆heteroalkyl, substituted or unsubstituted            C₃-C₁₀cycloalkyl, substituted or unsubstituted            C₂-C₁₀heterocycloalkyl, substituted or unsubstituted phenyl,            or substituted or unsubstituted monocyclic heteroaryl;        -   m is 0, 1, or 2;    -   L¹ is absent, C₁-C₆alkylene, C₁-C₆fluoroalkylene, or        C₃-C₆cycloalkylene;    -   Q is —CO₂H, —CO₂(C₁-C₆alkyl), —OH, —CN, —B(OH)₂, —C(═O)NHSO₂R⁹,        —C(═O)N(R¹⁰)₂, —SO₂NHC(═O)R⁹, —CN, tetrazolyl, —OP(═O)(OH)₂,        —P(═O)(OH)₂ or carboxylic acid bioisostere;    -   L² is absent, C₁-C₄alkylene, or C₃-C₇cycloalkylene;    -   L³ is —S—, S(═O), S(═O)₂, or —O—;    -   Ring B is a monocyclic aryl, bicyclic aryl, monocyclic        heteroaryl or bicyclic heteroaryl;        -   each R^(B) is independently H, halogen, —CN, —NO₂, —OH,            —OR⁹, —SR⁹, —S(═O)R⁹, —S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂,            —NR¹⁰S(═O)₂R⁹, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —OCO₂R⁹,            —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —OC(═O)N(R¹⁰)₂, —NHC(═O)R⁹,            —NHC(═O)OR⁹, C₁-C₆alkyl, C₁-C₆fluoroalkyl,            C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, substituted or            unsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstituted            C₂-C₁₀heterocycloalkyl, substituted or unsubstituted phenyl,            C₁-C₄alkylene-(substituted or unsubstituted phenyl),            substituted unsubstituted monocyclic heteroaryl,            C₁-C₄alkylene-(substituted or unsubstituted monocyclic            heteroaryl), a substituted or unsubstituted bicyclic            heteroaryl, or C₁-C₄alkylene-(substituted or unsubstituted            bicyclic heteroaryl);    -   n is 0, 1, or 2; R⁹ is C₁-C₆alkyl, C₁-C₆fluoroalkyl,        C₁-C₆deuteroalkyl, C₃-C₆cycloalkyl, a substituted or        unsubstituted phenyl, a substituted or unsubstituted monocyclic        heteroaryl, or a substituted or unsubstituted bicyclic        heteroaryl;    -   each R¹⁰ is independently selected from H, C₁-C₆alkyl,        C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl, C₃-C₆cycloalkyl, a        substituted or unsubstituted phenyl, or a substituted or        unsubstituted monocyclic heteroaryl; or    -   two R¹⁰ groups attached to the same N atom are taken together        with the N atom to which they are attached to form a substituted        or unsubstituted heterocycle.

For any and all of the embodiments, substituents are selected from amonga subset of the listed alternatives. For example, in some embodiments, Xis —O—, —S—, —S(═O)—, or —S(═O)₂—. In other embodiments, X is —O— or—S—. In other embodiments, X is —S—, —S(═O)—, or —S(═O)₂—. In someembodiments, X is —S—.

In some embodiments, R¹ is —F, —Cl, —Br, —CN, vinyl, cyclopropyl,cyclobutyl, —NH₂, —NH(CH₃), —N(CH₃)₂, —O—CH₃, or —S—CH₃.

In some embodiments, R¹ is vinyl, cyclopropyl, or cyclobutyl.

In some embodiments, R¹ is cyclopropyl, or cyclobutyl.

In some embodiments, R¹ is —F, —Cl, or —Br.

In some embodiments, L² is absent, or C₁-C₄alkylene; L³ is —S—, S(═O),or S(═O)₂.

In some embodiments, L² is absent, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, or—CH(CH₃)—.

In some embodiments, L¹ is absent, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—,—CH(CH₃)—, —CH(CH₂CH₃)—, —C(CH₃)₂—, —C(CH₂CH₃)₂—, cyclopropyl-1,1-diyl,cyclobutyl-1,1-diyl, cyclopentyl-1,1-diyl or cyclohexyl-1,1-diyl; Q is—CO₂H, —CO₂(C₁-C₆alkyl), —C(═O)NHSO₂R⁹ or tetrazolyl.

In some embodiments, L¹ is absent or —CH₂—; Q is —CO₂H, or—CO₂(C₁-C₆alkyl).

In some embodiments, the compound of Formula (I) has the followingstructure of Formula (II):

or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, Ring A is phenyl, naphthyl, monocyclic heteroarylcontaining 1-4 N atoms and 0 or 1 O or S atoms, monocyclic heteroarylcontaining 0-4 N atoms and 1 O or S atoms, bicyclic heteroarylcontaining 1-4 N atoms and 0 or 1 O or S atoms, or bicyclic heteroarylcontaining 0-4 N atoms and 1 O or S atoms; Ring B is phenyl, naphthyl,monocyclic heteroaryl containing 1-4 N atoms and 0 or 1 O or S atoms,monocyclic heteroaryl containing 0-4 N atoms and 1 O or S atoms,bicyclic heteroaryl containing 1-4 N atoms and 0 or 1 O or S atoms, orbicyclic heteroaryl containing 0-4 N atoms and 1 O or S atoms.

In some embodiments, Ring A is phenyl, naphthyl, furanyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, indolyl,indazolyl, benzoxazolyl, benzisoxazolyl, benzofuranyl, benzothienyl,benzothiazolyl, benzimidazolyl, purinyl, cinnolinyl, phthalazinyl,pteridinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, or azaindolyl.

In some embodiments, Ring A is phenyl or naphthyl.

In some embodiments, Ring A is furanyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, or triazinyl.

In some embodiments, Ring A is pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, or triazinyl.

In some embodiments, Ring A is furanyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, or thiadiazolyl.

In some embodiments, Ring A is quinolinyl, isoquinolinyl, quinazolinyl,quinoxalinyl, naphthyridinyl, indolyl, indazolyl, benzoxazolyl,benzisoxazolyl, benzofuranyl, benzothienyl, benzothiazolyl,benzimidazolyl, purinyl, cinnolinyl, phthalazinyl, pteridinyl,pyridopyrimidinyl, pyrazolopyrimidinyl, or azaindolyl.

In some embodiments, each R^(A) is H, halogen, —CN, —OH, —OR⁹, —SR⁹,C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl.

In some embodiments, L³ is —S—.

In some embodiments, L² is absent.

In some embodiments, the compound of Formula (I) or Formula (II) has thefollowing structure of Formula (III):

wherein,

W is CH, CF or N;

or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, L¹ is absent; and Q is —CO₂H.

In some embodiments, described herein is a compound of Formula (III), ora pharmaceutically acceptable salt, or solvate thereof:

-   -   wherein,    -   R¹ is —Cl, —Br, —CN, or C₃-C₆cyloalkyl;    -   R² is H, halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R⁹,        —S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, C₁-C₄alkyl, C₁-C₄fluoroalkyl,        C₁-C₄deuteroalkyl, or C₃-C₆cycloalkyl;    -   R³ is H, halogen, —CN, —OH, C₁-C₄alkyl, C₁-C₄fluoroalkyl,        C₁-C₄deuteroalkyl, C₁-C₄alkoxy, or C₁-C₄fluoroalkoxy;    -   W is CH, CF or N;    -   each R^(A) is H, halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R⁹,        —S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, C₁-C₆alkyl, or C₁-C₆fluoroalkyl;    -   L¹ is absent, C₁-C₆alkylene, or C₃-C₆cycloalkylene;    -   Q is —CO₂H, —CO₂(C₁-C₆alkyl), —OH, —CN, —B(OH)₂, —C(═O)NHSO₂R⁹,        —C(═O)N(R¹⁰)₂, —SO₂NHC(═O)R⁹, —CN, tetrazolyl, —OP(═O)(OH)₂,        —P(═O)(OH)₂ or carboxylic acid bioisostere;    -   Ring B is a monocyclic heteroaryl;        -   each R^(B) is independently H, halogen, —CN, —NO₂, —OH,            —OR⁹, —SR⁹, —S(═O)R⁹, —S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, C₁-C₆alkyl,            C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl,            substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted            or unsubstituted C₂-C₁₀heterocycloalkyl, substituted or            unsubstituted phenyl, C₁-C₄alkylene-(substituted or            unsubstituted phenyl), substituted unsubstituted monocyclic            heteroaryl, C₁-C₄alkylene-(substituted or unsubstituted            monocyclic heteroaryl), a substituted or unsubstituted            bicyclic heteroaryl, or C₁-C₄alkylene-(substituted or            unsubstituted bicyclic heteroaryl);        -   n is 0, 1, or 2;    -   R⁹ is C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl,        C₃-C₆cycloalkyl, a substituted or unsubstituted phenyl, a        substituted or unsubstituted monocyclic heteroaryl, or a        substituted or unsubstituted bicyclic heteroaryl;    -   each R¹⁰ is independently H, C₁-C₆alkyl, C₁-C₆fluoroalkyl,        C₁-C₆deuteroalkyl, C₃-C₆cycloalkyl, a substituted or        unsubstituted phenyl, or a substituted or unsubstituted        monocyclic heteroaryl; or    -   two R¹⁰ groups attached to the same N atom are taken together        with the N atom to which they are attached to form a substituted        or unsubstituted heterocycle.

In some embodiments, R¹ is —Cl, —Br, —CN, or cyclopropyl. In someembodiments, R¹ is cyclopropyl. In some embodiments, R¹ is —Cl.

In some embodiments, L¹ is absent, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—,—CH(CH₃)—, —CH(CH₂CH₃)—, —C(CH₃)₂—, —C(CH₂CH₃)₂—, cyclopropyl-1,1-diyl,cyclobutyl-1,1-diyl, cyclopentyl-1,1-diyl or cyclohexyl-1,1-diyl; and Qis —CO₂H, —CO₂(C₁-C₆alkyl), —C(═O)NHSO₂R⁹ or tetrazolyl.

In some embodiments, L¹ is absent, —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, orcyclopropyl-1,1-diyl; and Q is —CO₂H, or —CO₂(C₁-C₆alkyl).

In some embodiments, L¹ is absent, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—,—CH(CH₃)—, —CH(CH₂CH₃)—, —C(CH₃)₂—, or —C(CH₂CH₃)₂—. In someembodiments, L¹ is absent, —CH₂—, —CH(CH₃)—, —CH(CH₂CH₃)—, —C(CH₃)₂—, or—C(CH₂CH₃)₂—. In some embodiments, L¹ is absent, —CH₂—, —CH(CH₃)—, or—C(CH₃)₂—. In some embodiments, L¹ is absent, or —CH₂—.

In some embodiments, L¹ is —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH(CH₃)—,—CH(CH₂CH₃)—, —C(CH₃)₂—, or —C(CH₂CH₃)₂—. In some embodiments, L¹ is—CH₂—, —CH(CH₃)—, —CH(CH₂CH₃)—, —C(CH₃)₂—, or —C(CH₂CH₃)₂—. In someembodiments, L¹ is —CH₂—, —CH(CH₃)—, or —C(CH₃)₂—. In some embodiments,L¹ is —CH₂—.

In some embodiments, L¹ is absent or —CH₂—; and Q is —CO₂H, or—CO₂(C₁-C₆alkyl).

In some embodiments, Ring B is monocyclic heteroaryl containing 1-4 Natoms and 0 or 1 O or S atoms, or monocyclic heteroaryl containing 0-4 Natoms and 1 O or S atoms.

In some embodiments, Ring B is furanyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, or triazinyl.

In some embodiments, each R^(A) is H, halogen, —CN, —OH, —OR⁹, —SR⁹,C₁-C₆alkyl, or C₁-C₆fluoroalkyl.

In some embodiments, L¹ is absent, —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, orcyclopropyl-1,1-diyl; and Q is —CO₂H.

In some embodiments, L¹ is absent; and Q is —CO₂H.

In some embodiments, the compound or Formula (III) has the followingstructure:

or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, R² is H, F, Cl, Br, I, —CN, —OH, —CH₃, —CF₃, —CD₃,—OCH₃, —OCH₂CH₃, —OCF₃, or —OCH₂CF₃; R³ is H, F, Cl, Br, I, —CN, —OH,—CH₃, —CF₃, —CD₃, —OCH₃, —OCH₂CH₃, —OCF₃, or —OCH₂CF₃.

In some embodiments, R² is Cl; R³ is H, F, or Cl.

In some embodiments, Ring B is furanyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, or triazinyl.

In some embodiments, Ring B is pyrazolyl.

In some embodiments, the compound of Formula (III) has the followingstructure:

or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, R^(A) is H, halogen, —CN, —OH, —OR⁹, —SR⁹,C₁-C₆alkyl, or C₁-C₆fluoroalkyl;

R^(B) is H, C₁-C₆alkyl, C₁-C₆fluoroalkyl, or C₁-C₆deuteroalkyl; R¹ is—Cl, —Br, —CN, or cyclopropyl; R² is H, halogen, —CN, —OH, C₁-C₄alkyl,C₁-C₄fluoroalkyl, C₁-C₄deuteroalkyl, C₁-C₄alkoxy, or C₁-C₄fluoroalkoxy;and R³ is H, halogen, —CN, —OH, C₁-C₄alkyl, C₁-C₄fluoroalkyl,C₁-C₄deuteroalkyl, C₁-C₄alkoxy, or C₁-C₄fluoroalkoxy.

In some embodiments, R¹ is —Cl, or —Br. In some embodiments, R¹ iscyclopropyl.

In some embodiments, the compound of Formula (III) has the followingstructure:

or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, the compound of Formula (III) has the followingstructure:

or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, R^(A) is H, F, Cl, Br, I, —CN, —OH, —OCH₃,—OCH₂CH₃, —OCF₃, —OCH₂CF₃, —CH₃, —CH₂CH₃, —CF₃, or —CD₃.

In some embodiments, R^(B) is C₁-C₆alkyl.

In some embodiments, R² is H, F, Cl, Br, I, —CN, —OH, —CH₃, —CF₃, —CD₃,—OCH₃, —OCH₂CH₃, —OCF₃, or —OCH₂CF₃; R³ is H, F, Cl, Br, I, —CN, —OH,—CH₃, —CF₃, —CD₃, —OCH₃, —OCH₂CH₃, —OCF₃, or —OCH₂CF₃.

In some embodiments, R² is Cl; R³ is H, F, or Cl.

In some embodiments, L¹ is absent, —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, orcyclopropyl-1,1-diyl.

In some embodiments, L¹ is absent.

In some embodiments, the compound of Formula (I), Formula (II), orFormula (III) has the following structure of Formula (IV):

wherein,

W is CH, CF or N;

or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, R² is H, halogen, —CN, —OH, C₁-C₄alkyl,C₁-C₄fluoroalkyl, C₁-C₄deuteroalkyl, C₁-C₄alkoxy, C₁-C₄fluoroalkoxy, orC₁-C₄hydroxyalkyl.

In some embodiments, R² is H, F, Cl, Br, I, —CN, —OH, —CH₃, —CF₃, —CD₃,—OCH₃, —OCH₂CH₃, —OCF₃, —OCH₂CF₃, or —CH₂OH.

In some embodiments, R² is Cl.

In some embodiments, R³ is H, halogen, —CN, —OH, C₁-C₄alkyl,C₁-C₄fluoroalkyl, C₁-C₄deuteroalkyl, C₁-C₄alkoxy, C₁-C₄fluoroalkoxy, orC₁-C₄hydroxyalkyl.

In some embodiments, R³ is H, F, Cl, Br, I, —CN, —OH, —CH₃, —CF₃, —CD₃,—OCH₃, —OCH₂CH₃, —OCF₃, —OCH₂CF₃, or —CH₂OH.

In some embodiments, R³ is H, F, or Cl.

In some embodiments, Ring B is phenyl, naphthyl, furanyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, indolyl,indazolyl, benzoxazolyl, benzisoxazolyl, benzofuranyl, benzothienyl,benzothiazolyl, benzimidazolyl, purinyl, cinnolinyl, phthalazinyl,pteridinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, or azaindolyl.

In some embodiments, Ring B is phenyl or naphthyl.

In some embodiments, Ring B is furanyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, or triazinyl.

In some embodiments, Ring B is furanyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, or thiadiazolyl.

In some embodiments, Ring B is pyrazolyl.

In some embodiments, Ring B is pyrazolyl; and each R^(B) isindependently H, C₁-C₆alkyl, C₁-C₆fluoroalkyl, or C₁-C₆deuteroalkyl; nis 1.

In some embodiments, Ring B is pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, or triazinyl.

In some embodiments, Ring B is quinolinyl, isoquinolinyl, quinazolinyl,quinoxalinyl, naphthyridinyl, indolyl, indazolyl, benzoxazolyl,benzisoxazolyl, benzofuranyl, benzothienyl, benzothiazolyl,benzimidazolyl, purinyl, cinnolinyl, phthalazinyl, pteridinyl,pyridopyrimidinyl, pyrazolopyrimidinyl, or azaindolyl.

In some embodiments, the compound of Formula (I) has the followingstructure of Formula (V):

wherein,

W is CH, CF or N;

or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, R^(A) is H, halogen, —CN, —OH, —OR⁹, —SR⁹,C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl; R^(B)is H, C₁-C₆alkyl, C₁-C₆fluoroalkyl, or C₁-C₆deuteroalkyl; R¹ is —F, —Cl,—Br, —CN, C₃-C₆cyloalkyl, —NH₂, or —O—C₁-C₄ alkyl; R² is H, halogen,—CN, —OH, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄deuteroalkyl, C₁-C₄alkoxy,C₁-C₄fluoroalkoxy, or C₁-C₄hydroxyalkyl; R³ is H, halogen, —CN, —OH,C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄deuteroalkyl, C₁-C₄alkoxy,C₁-C₄fluoroalkoxy, or C₁-C₄hydroxyalkyl.

In some embodiments, R¹ is —F, —Cl, —Br, —CN, cyclopropyl, —NH₂, or—O—CH₃. In some embodiments, R¹ is —F, —Cl, or —Br. In some embodiments,R¹ is —Cl. In some embodiments, R¹ is C₃-C₆cyloalkyl. In someembodiments, R¹ is cyclopropyl.

In some embodiments, the compound of Formula (I) or Formula (V) has thefollowing structure of Formula (VI):

wherein,

W is CH, CF or N;

or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, the compound of Formula (I) or Formula (V) has thefollowing structure of Formula (VII):

wherein,

W is CH, CF or N;

or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, R^(A) is H, F, Cl, Br, I, —CN, —OH, —OCH₃,—OCH₂CH₃, —OCF₃, —OCH₂CF₃, —CH₃, —CH₂CH₃, —CF₃, or —CD₃. In someembodiments, R^(A) is H.

In some embodiments, R^(B) is C₁-C₆alkyl. In some embodiments, R^(B) is—CH₃, —CH₂CH₃, or —CH₂CH₂CH₃, or —CH(CH₃)₂.

In some embodiments, R² is H, F, Cl, Br, I, —CN, —OH, —CH₃, —CF₃, —CD₃,—OCH₃, —OCH₂CH₃, —OCF₃, —OCH₂CF₃, or —CH₂OH. In some embodiments, R² isCl.

In some embodiments, R³ is H, F, Cl, Br, I, —CN, —OH, —CH₃, —CF₃, —CD₃,—OCH₃, —OCH₂CH₃, —OCF₃, —OCH₂CF₃, or —CH₂OH. In some embodiments, R³ isH, F, or Cl.

In some embodiments, W is CH, CF or N. In some embodiments, W is CH. Insome embodiments, W is CH or CF. In some embodiments, W is CF. In someembodiments, W is N.

In some embodiments, the compound of Formula (I) has the followingstructure:

wherein,

W is CH, CF or N;

or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, R¹ is —Cl or cyclopropyl. In some embodiments, R¹is —Cl. In some embodiments, R¹ is cyclopropyl.

In some embodiments, R¹ is as described in Tables 1 and 2. In someembodiments, R³ is as described in Tables 1 and 2. In some embodiments,R^(B) is as described in Tables 1 and 2. In some embodiments, R¹, R³ andR^(B) are as described in Tables 1 and 2. In some embodiments, L¹ is asdescribed in Table 2.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof are chosen by one skilled in the field to providestable moieties and compounds.

Exemplary compounds include the following compounds:

TABLE 1

Compound no. R^(B) R¹ W R³ 1-1 1-propyl —Cl CH H 1-2 1-propyl —Br CH H1-3 1-propyl —CN CH H 1-4 1-propyl c-C₃H₅ CH H 1-5 1-propyl —NH₂ CH H1-6 1-propyl —OMe CH H 1-7 1-propyl —Cl CH F 1-8 1-propyl —Br CH F 1-91-propyl —CN CH F 1-10 1-propyl c-C₃H₅ CH F 1-11 1-propyl —NH₂ CH F 1-121-propyl —OMe CH F 1-13 1-propyl —Cl CF F 1-14 1-propyl —Br CF F 1-151-propyl —CN CF F 1-16 1-propyl c-C₃H₅ CF F 1-17 1-propyl —NH₂ CF F 1-181-propyl —OMe CF F 1-19 ethyl —Cl CH H 1-20 ethyl —Br CH H 1-21 ethyl—CN CH H 1-22 ethyl c-C₃H₅ CH H 1-23 ethyl —NH₂ CH H 1-24 ethyl —OMe CHH 1-25 ethyl —Cl CH F 1-26 ethyl —Br CH F 1-27 ethyl —CN CH F 1-28 ethylc-C₃H₅ CH F 1-29 ethyl —NH₂ CH F 1-30 ethyl —OMe CH F 1-31 ethyl —Cl CFF 1-32 ethyl —Br CF F 1-33 ethyl —CN CF F 1-34 ethyl c-C₃H₅ CF F 1-35ethyl —NH₂ CF F 1-36 ethyl —OMe CF F 1-37 methyl —Cl CH H 1-38 methyl—Br CH H 1-39 methyl —CN CH H 1-40 methyl c-C₃H₅ CH H 1-41 methyl —NH₂CH H 1-42 methyl —OMe CH H 1-43 methyl —Cl CH F 1-44 methyl —Br CH F1-45 methyl —CN CH F 1-46 methyl c-C₃H₅ CH F 1-47 methyl —NH₂ CH F 1-48methyl —OMe CH F 1-49 methyl —Cl CF F 1-50 methyl —Br CF F 1-51 methyl—CN CF F 1-52 methyl c-C₃H₅ CF F 1-53 methyl —NH₂ CF F 1-54 2-propyl —ClCH H 1-55 2-propyl —Br CH H 1-56 2-propyl —CN CH H 1-57 2-propyl c-C₃H₅CH H 1-58 2-propyl —NH₂ CH H 1-59 2-propyl —OMe CH H 1-60 2-propyl —ClCH F 1-61 2-propyl —Br CH F 1-62 2-propyl —CN CH F 1-63 2-propyl c-C₃H₅CH F 1-64 2-propyl —NH₂ CH F 1-65 2-propyl —OMe CH F 1-66 2-propyl —ClCF F 1-67 2-propyl —Br CF F 1-68 2-propyl —CN CF F 1-69 2-propyl c-C₃H₅CF F 1-70 2-propyl —NH₂ CF F 1-71 1-propyl —Cl N H 1-72 1-propyl —Br N H1-73 1-propyl —CN N H 1-74 1-propyl c-C₃H₅ N H 1-75 1-propyl —NH₂ N H1-76 1-propyl —OMe N H 1-77 1-propyl —Cl N F 1-78 1-propyl —Br N F 1-791-propyl —CN N F 1-80 1-propyl c-C₃H₅ N F 1-81 1-propyl —NH₂ N F 1-821-propyl —OMe N F 1-83 ethyl —Cl N H 1-84 ethyl —Br N H 1-85 ethyl —CN NH 1-86 ethyl c-C₃H₅ N H 1-87 ethyl —NH₂ N H 1-88 ethyl —OMe N H 1-89ethyl —Cl N F 1-90 ethyl —Br N F 1-91 ethyl —CN N F 1-92 ethyl c-C₃H₅ NF 1-93 ethyl —NH₂ N F 1-94 ethyl —OMe N F 1-95 methyl —Cl N H 1-96methyl —Br N H 1-97 methyl —CN N H 1-98 methyl c-C₃H₅ N H 1-99 methyl—NH₂ N H 1-100 methyl —OMe N H 1-101 methyl —Cl N F 1-102 methyl —Br N F1-103 methyl —CN N F 1-104 methyl c-C₃H₅ N F 1-105 methyl —NH₂ N F 1-106methyl —OMe N F 1-107 2-propyl —Cl N H 1-108 2-propyl —Br N H 1-1092-propyl —CN N H 1-110 2-propyl c-C₃H₅ N H 1-111 2-propyl —NH₂ N H 1-1122-propyl —OMe N H 1-113 2-propyl —Cl N F 1-114 2-propyl —Br N F 1-1152-propyl —CN N F 1-116 2-propyl c-C₃H₅ N F 1-117 2-propyl —NH₂ N F 1-1182-propyl —OMe N F 1-119 H c-C₃H₅ CF F 1-120 -CH₂CH₂OH c-C₃H₅ CF F 1-121-CH₂CH₂OC(O)NH₂ c-C₃H₅ CF F 1-122 -CH₂CH₂NH₂ c-C₃H₅ CF F 1-123-CH₂CH₂NHC(O)NH₂ c-C₃H₅ CF F 1-124 -CH₂CH₂CH₂CO₂H c-C₃H₅ CF F 1-125-CH₂CH₂CH₂CONH₂ c-C₃H₅ CF F 1-126 -CH₂CF₃ c-C₃H₅ CF F 1-127 -CD₂CD₃c-C₃H₅ CF F 1-128 -(CH₂)₆NH₂ c-C₃H₅ CF F 1-129 -(CH₂)₄CCH c-C₃H₅ CF F1-130 -CH₂C(CH₃)₂CH₂OH c-C₃H₅ CF F 1-131 -(CH₂)₆NHC(O)N- fluoresceinc-C₃H₅ CF F 1-132 -CH₂CH₂CH₂C(O)NHCH₃ c-C₃H₅ CF F 1-133-CH₂CH₂CH₂C(O)NH(CH₃)₂ c-C₃H₅ CF F 1-134 -CH₂CH₂C(CH₃)₂C(O)NH₂ c-C₃H₅ CFF 1-135 -CH₂CH₂CH₂C(O)NH₂ c-C₃H₅ N F 1-136 -CH₂CH₂CH₂C(O)NHCH₃ c-C₃H₅ NF 1-137 -CH₂CH₂CH₂C(O)NH(CH₃)₂ c-C₃H₅ N F 1-138 -CH₂CH₂C(CH₃)₂C(O)NH₂c-C₃H₅ N F

Compounds in Table 1 are named:

-   3-((2,6-dichloro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-1);-   3-((2-bromo-6-chloro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-2);-   3-((6-chloro-2-cyano-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-3);-   3-((6-chloro-2-cyclopropyl-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-4);-   3-((2-amino-6-chloro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-5);-   3-((6-chloro-2-methoxy-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-6);-   3-((2,6-dichloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-7);-   3-((2-bromo-6-chloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-8);-   3-((6-chloro-2-cyano-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-9);-   3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-10);-   3-((2-amino-6-chloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-11);-   3-((6-chloro-7-fluoro-2-methoxy-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-12);-   3-((2,6-dichloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-13);-   3-((2-bromo-6-chloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-14);-   3-((6-chloro-2-cyano-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-15);-   3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-16);-   3-((2-amino-6-chloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-17);-   3-((6-chloro-7-fluoro-2-methoxy-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-18);-   3-((2,6-dichloro-1-(1-ethyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-19);-   3-((2-bromo-6-chloro-1-(1-ethyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-20);-   3-((6-chloro-2-cyano-1-(1-ethyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-21);-   3-((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-22);-   3-((2-amino-6-chloro-1-(1-ethyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-23);-   3-((6-chloro-2-methoxy-1-(1-ethyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-24);-   3-((2,6-dichloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-25);-   3-((2-bromo-6-chloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-26);-   3-((6-chloro-2-cyano-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-27);-   3-((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-28);-   3-((2-amino-6-chloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-29);-   3-((6-chloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-2-methoxy-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-30);-   3-((2,6-dichloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-31);-   3-((2-bromo-6-chloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-32);-   3-((6-chloro-2-cyano-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-33);-   3-((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-34);-   3-((2-amino-6-chloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-35);-   3-((6-chloro-2-methoxy-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-36);-   3-((2,6-dichloro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-37);-   3-((2-bromo-6-chloro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-38);-   3-((6-chloro-2-cyano-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-39);-   3-((6-chloro-2-cyclopropyl-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-40);-   3-((2-amino-6-chloro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-41);-   3-((6-chloro-2-methoxy-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-42);-   3-((2,6-dichloro-7-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-43);-   3-((2-bromo-6-chloro-7-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-44);-   3-((6-chloro-2-cyano-7-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-45);-   3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-46);-   3-((2-amino-6-chloro-7-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-47);-   3-((6-chloro-7-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-2-methoxy-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-48);-   3-((2,6-dichloro-7-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-49);-   3-((2-bromo-6-chloro-7-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-50);-   3-((6-chloro-2-cyano-7-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-51);-   3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-52);-   3-((2-amino-6-chloro-7-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-53);-   3-((2,6-dichloro-1-(1-isopropyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-54);-   3-((2-bromo-6-chloro-1-(1-isopropyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-55);-   3-((6-chloro-2-cyano-1-(1-isopropyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-56);-   3-((6-chloro-2-cyclopropyl-1-(1-isopropyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-57);-   3-((2-amino-6-chloro-1-(1-isopropyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-58);-   3-((6-chloro-2-methoxy-1-(1-isopropyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-59);-   3-((2,6-dichloro-7-fluoro-1-(1-isopropyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-60);-   3-((2-bromo-6-chloro-7-fluoro-1-(1-isopropyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-61);-   3-((6-chloro-2-cyano-7-fluoro-1-(1-isopropyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-62);-   3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-isopropyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-63);-   3-((2-amino-6-chloro-7-fluoro-1-(1-isopropyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-64);-   3-((6-chloro-7-fluoro-1-(1-isopropyl-1H-pyrazol-4-yl)-2-methoxy-1H-indol-3-yl)thio)benzoic    acid (compound no. 1-65);-   3-((2,6-dichloro-7-fluoro-1-(1-isopropyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-66);-   3-((2-bromo-6-chloro-7-fluoro-1-(1-isopropyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-67);-   3-((6-chloro-2-cyano-7-fluoro-1-(1-isopropyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-68);-   3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-isopropyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-69);-   3-((2-amino-6-chloro-7-fluoro-1-(1-isopropyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-70);-   6-((2,6-dichloro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-71);-   6-((2-bromo-6-chloro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-72);-   6-((6-chloro-2-cyano-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-73);-   6-((6-chloro-2-cyclopropyl-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-74);-   6-((2-amino-6-chloro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-75);-   6-((6-chloro-2-methoxy-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-76);-   6-((2,6-dichloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-77);-   6-((2-bromo-6-chloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-78);-   6-((6-chloro-2-cyano-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-79);-   6-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-80);-   6-((2-amino-6-chloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-81);-   6-((6-chloro-7-fluoro-2-methoxy-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-82);-   6-((2,6-dichloro-1-(1-ethyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-83);-   6-((2-bromo-6-chloro-1-(1-ethyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-84);-   6-((6-chloro-2-cyano-1-(1-ethyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-85);-   6-((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-86);-   6-((2-amino-6-chloro-1-(1-ethyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-87);-   6-((6-chloro-1-(1-ethyl-1H-pyrazol-4-yl)-2-methoxy-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-88);-   6-((2,6-dichloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-89);-   6-((2-bromo-6-chloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-90);-   6-((6-chloro-2-cyano-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-91);-   6-((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-92);-   6-((2-amino-6-chloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-93);-   6-((6-chloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-2-methoxy-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-94);-   6-((2,6-dichloro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-95);-   6-((2-bromo-6-chloro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-96);-   6-((6-chloro-2-cyano-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-97);-   6-((6-chloro-2-cyclopropyl-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-98);-   6-((2-amino-6-chloro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-99);-   6-((6-chloro-2-methoxy-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-100);-   6-((2,6-dichloro-7-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-101);-   6-((2-bromo-6-chloro-7-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-102);-   6-((6-chloro-2-cyano-7-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-103);-   6-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-104);-   6-((2-amino-6-chloro-7-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-105);-   6-((6-chloro-7-fluoro-2-methoxy-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-106);-   6-((2,6-dichloro-1-(1-isopropyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-107);-   6-((2-bromo-6-chloro-1-(1-isopropyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-108);-   6-((6-chloro-2-cyano-1-(1-isopropyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-109);-   6-((6-chloro-2-cyclopropyl-1-(1-isopropyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-110;-   6-((2-amino-6-chloro-1-(1-isopropyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-111);-   6-((6-chloro-1-(1-isopropyl-1H-pyrazol-4-yl)-2-methoxy-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-112);-   6-((2,6-dichloro-7-fluoro-1-(1-isopropyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-113);-   6-((2-bromo-6-chloro-7-fluoro-1-(1-isopropyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-114);-   6-((6-chloro-2-cyano-7-fluoro-1-(1-isopropyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-115);-   6-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-isopropyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-116);-   6-((2-amino-6-chloro-7-fluoro-1-(1-isopropyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-117);-   6-((6-chloro-7-fluoro-1-(1-isopropyl-1H-pyrazol-4-yl)-2-methoxy-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-118);-   3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-119);-   3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-120);-   3-(1-(1-(2-(carbamoyloxy)ethyl)-1H-pyrazol-4-yl)-(6-chloro-2-cyclopropyl-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-121);-   3-(1-(1-(2-aminoethyl)-1H-pyrazol-4-yl)-(6-chloro-2-cyclopropyl-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-122);-   3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-(2-ureidoethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-123);-   3-(1-(1-(3-carboxypropyl)-1H-pyrazol-4-yl)-(6-chloro-2-cyclopropyl-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-124);-   3-(1-(1-(4-amino-4-oxobutyl)-1H-pyrazol-4-yl)-(6-chloro-2-cyclopropyl-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-125);-   3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-126);-   3-((6-chloro-2-cyclopropyl-1-(1-(²H₅)ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoic    acid; (compound no. 1-127);-   3-(1-(1-(6-aminohexyl)-1H-pyrazol-4-yl)-(6-chloro-2-cyclopropyl-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-128);-   3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-(hex-5-ynyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-129);-   3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-(3-hydroxy-2,2-dimethylpropyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-130);-   3-((6-chloro-2-cyclopropyl-1-(1-(6-(3-(3′,6′-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9′-xanthen]-5-yl)ureido)hexyl)-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-131);-   3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-(4-(methylamino)-4-oxobutyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 1-132);-   3-(6-chloro-2-cyclopropyl-1-(1-(4-(dimethylamino)-4-oxobutyl)-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-ylthio)-2-fluorobenzoic    acid (compound no. 1-133);-   3-(1-(1-(4-amino-3,3-dimethyl-4-oxobutyl)-1H-pyrazol-4-yl)-6-chloro-2-cyclopropyl-7-fluoro-1H-indol-3-ylthio)-2-fluorobenzoic    acid (compound no. 1-134);-   6-(1-(1-(4-amino-4-oxobutyl)-1H-pyrazol-4-yl)-(6-chloro-2-cyclopropyl-7-fluoro-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-135);-   6-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-(4-(methylamino)-4-oxobutyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-136);-   6-((6-chloro-2-cyclopropyl-1-(1-(4-(dimethylamino)-4-oxobutyl)-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-137);-   6-(1-(1-(4-amino-3,3-dimethyl-4-oxobutyl)-1H-pyrazol-4-yl)-(6-chloro-2-cyclopropyl-7-fluoro-1H-indol-3-yl)thio)picolinic    acid (compound no. 1-138).

TABLE 2

  Compound no.

    R1     W     L1 2-1 pyridin-3-yl —Cl CF absent 2-2 pyridin-3-yl —BrCF absent 2-3 pyridin-3-yl c-C₃H₅ CF absent 2-4 pyridin-3-yl —CN CFabsent 2-5 1-ethyl-1H-pyrazol-4-yl —Cl CF CH₂ 2-61-ethyl-1H-pyrazol-4-yl —Br CF CH₂ 2-7 1-ethyl-1H-pyrazol-4-yl c-C₃H₅ CFCH₂ 2-8 1-ethyl-1H-pyrazol-4-yl —CN CF CH₂ 2-9 1-ethyl-1H-pyrazol-4-yl—Cl CF C(CH₃)₂ 2-10 1-ethyl-1H-pyrazol-4-yl —Br CF C(CH₃)₂ 2-111-ethyl-1H-pyrazol-4-yl c-C₃H₅ CF C(CH₃)₂ 2-12 1-ethyl-1H-pyrazol-4-yl—CN CF C(CH₃)₂ 2-13 1-ethyl-1H-pyrazol-4-yl —Cl CF C(CH₂CH₂)₂ 2-141-ethyl-1H-pyrazol-4-yl —Br CF C(CH₂CH₂)₂ 2-15 1-ethyl-1H-pyrazol-4-ylc-C₃H₅ CF C(CH₂CH₂)₂ 2-16 1-ethyl-1H-pyrazol-4-yl —CN CF C(CH₂CH₂)₂ 2-171-propyl-1H-pyrazol-4-yl —Cl CF CH₂ 2-18 1-propyl-1H-pyrazol-4-yl —Br CFCH₂ 2-19 1-propyl-1H-pyrazol-4-yl c-C₃H₅ CF CH₂ 2-201-propyl-1H-pyrazol-4-yl —CN CF CH₂ 2-21 1-propyl-1H-pyrazol-4-yl —Cl CFC(CH₃)₂ 2-22 1-propyl-1H-pyrazol-4-yl —Br CF C(CH₃)₂ 2-231-propyl-1H-pyrazol-4-yl c-C₃H₅ CF C(CH₃)₂ 2-24 1-propyl-1H-pyrazol-4-yl—CN CF C(CH₃)₂ 2-25 1-propyl-1H-pyrazol-4-yl —Cl CF C(CH₂CH₂)₂ 2-261-propyl-1H-pyrazol-4-yl —Br CF C(CH₂CH₂)₂ 2-27 1-propyl-1H-pyrazol-4-ylc-C₃H₅ CF C(CH₂CH₂)₂ 2-28 1-propyl-1H-pyrazol-4-yl —CN CF C(CH₂CH₂)₂2-29 1-ethyl-1H-pyrazol-4-yl —Cl N CH₂ 2-30 1-ethyl-1H-pyrazol-4-yl —ClN C(CH₃)₂ 2-31 1-ethyl-1H-pyrazol-4-yl —Cl N C(CH₂CH₂)₂ 2-321-propyl-1H-pyrazol-4-yl —Cl N CH₂ 2-33 1-propyl-1H-pyrazol-4-yl —Cl NC(CH₃)₂ 2-34 1-propyl-1H-pyrazol-4-yl —Cl N C(CH₂CH₂)₂

-   Compounds in Table 2 are named:-   3-((2,6-dichloro-7-fluoro-1-(pyridin-3-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 2-1);-   3-((2-bromo-6-chloro-7-fluoro-1-(pyridin-3-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 2-2);-   3-((6-chloro-2-cyclopropyl-7-fluoro-1-(pyridin-3-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 2-3);-   3-((6-chloro-2-cyano-7-fluoro-1-(pyridin-3-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic    acid (compound no. 2-4);-   2-(3-((2,6-dichloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorophenyl)acetic    acid (compound no. 2-5);-   2-(3-((2-bromo-6-chloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorophenyl)acetic    acid (compound no. 2-6);-   2-(3-((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorophenyl)acetic    acid (compound no. 2-7);-   2-(3-((6-chloro-2-cyano-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorophenyl)acetic    acid (compound no. 2-8);-   2-(3-((2,6-dichloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorophenyl)-2-methylpropanoic    acid (compound no. 2-9);-   2-(3-((2-bromo-6-chloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorophenyl)-2-methylpropanoic    acid (compound no. 2-10);-   2-(3-((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorophenyl)-2-methylpropanoic    acid (compound no. 2-11);-   2-(3-((6-chloro-2-cyano-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorophenyl)-2-methylpropanoic    acid (compound no. 2-12)-   1-(3-((2,6-dichloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorophenyl)cyclopropanecarboxylic    acid (compound no. 2-13);-   1-(3-((2-bromo-6-chloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorophenyl)    cyclopropanecarboxylic acid (compound no. 2-14);-   1-(3-((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorophenyl)cyclopropanecarboxylic    acid (compound no. 2-15);-   1-(3-((6-chloro-2-cyano-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorophenyl)    cyclopropanecarboxylic acid (compound no. 2-16);-   2-(3-((2,6-dichloro-1-(1-propyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorophenyl)acetic    acid (compound no. 2-17);-   2-(3-((2-bromo-6-chloro-1-(1-propyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorophenyl)acetic    acid (compound no. 2-18);-   2-(3-((6-chloro-2-cyclopropyl-1-(1-propyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorophenyl)acetic    acid (compound no. 2-19);-   2-(3-((6-chloro-2-cyano-1-(1-propyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorophenyl)acetic    acid (compound no. 2-20);-   2-(3-((2,6-dichloro-1-(1-propyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorophenyl)-2-methylpropanoic    acid (compound no. 2-21);-   2-(3-((2-bromo-6-chloro-1-(1-propyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorophenyl)-2-methylpropanoic    acid (compound no. 2-22);-   2-(3-((6-chloro-2-cyclopropyl-1-(1-propyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorophenyl)-2-methylpropanoic    acid (compound no. 2-23);-   2-(3-((6-chloro-2-cyano-1-(1-propyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorophenyl)-2-methylpropanoic    acid (compound no. 2-24)-   1-(3-((2,6-dichloro-1-(1-propyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorophenyl)cyclopropanecarboxylic    acid (compound no. 2-25);-   1-(3-((2-bromo-6-chloro-1-(1-propyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorophenyl)    cyclopropanecarboxylic acid (compound no. 2-26);-   1-(3-((6-chloro-2-cyclopropyl-1-(1-propyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorophenyl)cyclopropanecarboxylic    acid (compound no. 2-27);-   1-(3-((6-chloro-2-cyano-1-(1-propyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorophenyl)    cyclopropanecarboxylic acid (compound no. 2-28);-   2-(6-((2,6-dichloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)pyridine-2-yl)acetic    acid (compound no. 2-29);-   2-(6-((2,6-dichloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)pyridine-2-yl)-2-methylpropanoic    acid (compound no. 2-30);-   1-(6-((2,6-dichloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)pyridine-2-yl)cyclopropanecarboxylic    acid (compound no. 2-31);-   2-(6-((2,6-dichloro-1-(1-propyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)pyridine-2-yl)acetic    acid (compound no. 2-32);-   2-(6-((2,6-dichloro-1-(1-propyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)pyridine-2-yl)-2-methylpropanoic    acid (compound no. 2-33);-   1-(6-((2,6-dichloro-1-(1-propyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)pyridine-2-yl)cyclopropanecarboxylic    acid (compound no. 2-34).

In one aspect, compounds described herein are in the form ofpharmaceutically acceptable salts. As well, active metabolites of thesecompounds having the same type of activity are included in the scope ofthe present disclosure. In addition, the compounds described herein canexist in unsolvated as well as solvated forms with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. The solvatedforms of the compounds presented herein are also considered to bedisclosed herein.

“Pharmaceutically acceptable,” as used herein, refers a material, suchas a carrier or diluent, which does not abrogate the biological activityor properties of the compound, and is relatively nontoxic, i.e., thematerial is administered to an individual without causing undesirablebiological effects or interacting in a deleterious manner with any ofthe components of the composition in which it is contained.

The term “pharmaceutically acceptable salt” refers to a form of atherapeutically active agent that consists of a cationic form of thetherapeutically active agent in combination with a suitable anion, or inalternative embodiments, an anionic form of the therapeutically activeagent in combination with a suitable cation. Handbook of PharmaceuticalSalts: Properties, Selection and Use. International Union of Pure andApplied Chemistry, Wiley-VCH 2002. S. M. Berge, L. D. Bighley, D. C.Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P. H. Stahl and C. G. Wermuth,editors, Handbook of Pharmaceutical Salts: Properties, Selection andUse, Weinheim/Zürich: Wiley-VCH/VHCA, 2002. Pharmaceutical saltstypically are more soluble and more rapidly soluble in stomach andintestinal juices than non-ionic species and so are useful in soliddosage forms. Furthermore, because their solubility often is a functionof pH, selective dissolution in one or another part of the digestivetract is possible and this capability can be manipulated as one aspectof delayed and sustained release behaviours. Also, because thesalt-forming molecule can be in equilibrium with a neutral form, passagethrough biological membranes can be adjusted.

In some embodiments, pharmaceutically acceptable salts are obtained byreacting a compound described herein with an acid. In some embodiments,the compound described herein (i.e. free base form) is basic and isreacted with an organic acid or an inorganic acid. Inorganic acidsinclude, but are not limited to, hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid.Organic acids include, but are not limited to, 1-hydroxy-2-naphthoicacid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid;2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid;acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L);benzenesulfonic acid; benzoic acid; camphoric acid (+);camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid(hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamicacid; citric acid; cyclamic acid; dodecylsulfuric acid;ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaricacid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconicacid (D); glucuronic acid (D); glutamic acid; glutaric acid;glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid;lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid(−L); malonic acid; mandelic acid (DL); methanesulfonic acid;naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinicacid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoricacid; proprionic acid; pyroglutamic acid (−L); salicylic acid; sebacicacid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+L);thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid.

In some embodiments, a compound described herein is prepared as achloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt,citrate salt or phosphate salt. In some embodiments, a compounddescribed herein is prepared as a hydrochloride salt.

In some embodiments, pharmaceutically acceptable salts are obtained byreacting a compound described herein with a base. In some embodiments,the compound described herein is acidic and is reacted with a base. Insuch situations, an acidic proton of the compound described herein isreplaced by a metal ion, e.g., lithium, sodium, potassium, magnesium,calcium, or an aluminum ion. In some cases, compounds described hereincoordinate with an organic base, such as, but not limited to,ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine,N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. Inother cases, compounds described herein form salts with amino acids suchas, but not limited to, arginine, lysine, and the like. Acceptableinorganic bases used to form salts with compounds that include an acidicproton, include, but are not limited to, aluminum hydroxide, calciumhydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,sodium hydroxide, lithium hydroxide, and the like. In some embodiments,the compounds provided herein are prepared as a sodium salt, calciumsalt, potassium salt, magnesium salt, meglumine salt, N-methylglucaminesalt or ammonium salt. In some embodiments, the compounds providedherein are prepared as a sodium salt.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms. In someembodiments, solvates contain either stoichiometric ornon-stoichiometric amounts of a solvent, and are formed during theprocess of crystallization with pharmaceutically acceptable solventssuch as water, ethanol, and the like. Hydrates are formed when thesolvent is water, or alcoholates are formed when the solvent is alcohol.Solvates of compounds described herein are conveniently prepared orformed during the processes described herein. In addition, the compoundsprovided herein optionally exist in unsolvated as well as solvatedforms.

The methods and formulations described herein include the use ofN-oxides (if appropriate), crystalline forms (also known as polymorphs),or pharmaceutically acceptable salts of compounds described herein, aswell as active metabolites of these compounds having the same type ofactivity.

In some embodiments, sites on the organic radicals (e.g. alkyl groups,aromatic rings) of compounds described herein are susceptible to variousmetabolic reactions. Incorporation of appropriate substituents on theorganic radicals will reduce, minimize or eliminate this metabolicpathway. In specific embodiments, the appropriate substituent todecrease or eliminate the susceptibility of the aromatic ring tometabolic reactions is, by way of example only, a halogen, deuterium, analkyl group, a haloalkyl group, or a deuteroalkyl group.

In another embodiment, the compounds described herein are labeledisotopically (e.g. with a radioisotope) or by another other means,including, but not limited to, the use of chromophores or fluorescentmoieties, bioluminescent labels, or chemiluminescent labels.

Compounds described herein include isotopically-labeled compounds, whichare identical to those recited in the various formulae and structurespresented herein, but for the fact that one or more atoms are replacedby an atom having an atomic mass or mass number different from theatomic mass or mass number usually found in nature. Examples of isotopesthat can be incorporated into the present compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, forexample, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F, ³⁶Cl. In one aspect,isotopically-labeled compounds described herein, for example those intowhich radioactive isotopes such as ³H and ¹⁴C are incorporated, areuseful in drug and/or substrate tissue distribution assays. In oneaspect, substitution with isotopes such as deuterium affords certaintherapeutic advantages resulting from greater metabolic stability, suchas, for example, increased in vivo half-life or reduced dosagerequirements.

In some embodiments, the compounds described herein possess one or morestereocenters and each stereocenter exists independently in either the Ror S configuration. The compounds presented herein include alldiastereomeric, enantiomeric, atropisomers, and epimeric forms as wellas the appropriate mixtures thereof. The compounds and methods providedherein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z)isomers as well as the appropriate mixtures thereof

Individual stereoisomers are obtained, if desired, by methods such as,stereoselective synthesis and/or the separation of stereoisomers bychiral chromatographic columns. In certain embodiments, compoundsdescribed herein are prepared as their individual stereoisomers byreacting a racemic mixture of the compound with an optically activeresolving agent to form a pair of diastereoisomeric compounds/salts,separating the diastereomers and recovering the optically pureenantiomers. In some embodiments, resolution of enantiomers is carriedout using covalent diastereomeric derivatives of the compounds describedherein. In another embodiment, diastereomers are separated byseparation/resolution techniques based upon differences in solubility.In other embodiments, separation of steroisomers is performed bychromatography or by the forming diastereomeric salts and separation byrecrystallization, or chromatography, or any combination thereof. JeanJacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates andResolutions”, John Wiley And Sons, Inc., 1981. In some embodiments,stereoisomers are obtained by stereoselective synthesis.

In some embodiments, compounds described herein are prepared asprodrugs. A “prodrug” refers to an agent that is converted into theparent drug in vivo. Prodrugs are often useful because, in somesituations, they are easier to administer than the parent drug. Theyare, for instance, bioavailable by oral administration whereas theparent is not. Further or alternatively, the prodrug also has improvedsolubility in pharmaceutical compositions over the parent drug. In someembodiments, the design of a prodrug increases the effective watersolubility. An example, without limitation, of a prodrug is a compounddescribed herein, which is administered as an ester (the “prodrug”) butthen is metabolically hydrolyzed to provide the active entity. A furtherexample of a prodrug is a short peptide (polyaminoacid) bonded to anacid group where the peptide is metabolized to reveal the active moiety.In certain embodiments, upon in vivo administration, a prodrug ischemically converted to the biologically, pharmaceutically ortherapeutically active form of the compound. In certain embodiments, aprodrug is enzymatically metabolized by one or more steps or processesto the biologically, pharmaceutically or therapeutically active form ofthe compound.

Prodrugs of the compounds described herein include, but are not limitedto, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives,N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines,N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters,and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A.Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.;Academic, 1985, vol. 42, p. 309-396; Bundgaard, H. “Design andApplication of Prodrugs” in A Textbook of Drug Design and Development,Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113-191; andBundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, each ofwhich is incorporated herein by reference. In some embodiments, ahydroxyl group in the compounds disclosed herein is used to form aprodrug, wherein the hydroxyl group is incorporated into an acyloxyalkylester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphateester, sugar ester, ether, and the like. In some embodiments, a hydroxylgroup in the compounds disclosed herein is a prodrug wherein thehydroxyl is then metabolized in vivo to provide a carboxylic acid group.In some embodiments, a carboxyl group is used to provide an ester oramide (i.e. the prodrug), which is then metabolized in vivo to provide acarboxylic acid group. In some embodiments, compounds described hereinare prepared as alkyl ester prodrugs.

Prodrug forms of the herein described compounds, wherein the prodrug ismetabolized in vivo to produce a compound described herein as set forthherein are included within the scope of the claims. In some cases, someof the herein-described compounds is a prodrug for another derivative oractive compound.

In additional or further embodiments, the compounds described herein aremetabolized upon administration to an organism in need to produce ametabolite that is then used to produce a desired effect, including adesired therapeutic effect.

A “metabolite” of a compound disclosed herein is a derivative of thatcompound that is formed when the compound is metabolized. The term“active metabolite” refers to a biologically active derivative of acompound that is formed when the compound is metabolized. The term“metabolized,” as used herein, refers to the sum of the processes(including, but not limited to, hydrolysis reactions and reactionscatalyzed by enzymes) by which a particular substance is changed by anorganism. Thus, enzymes may produce specific structural alterations to acompound. For example, cytochrome P450 catalyzes a variety of oxidativeand reductive reactions while uridine diphosphate glucuronyltransferasescatalyze the transfer of an activated glucuronic-acid molecule toaromatic alcohols, aliphatic alcohols, carboxylic acids, amines and freesulphydryl groups. Metabolites of the compounds disclosed herein areoptionally identified either by administration of compounds to a hostand analysis of tissue samples from the host, or by incubation ofcompounds with hepatic cells in vitro and analysis of the resultingcompounds.

Synthesis of Compounds

Compounds described herein are synthesized using standard synthetictechniques or using methods known in the art in combination with methodsdescribed herein.

Indoles are readily prepared by chemical synthesis using standardmethodologies as described in the review “Practical methodologies forthe synthesis of indoles” Humphrey and Kuethe, Chem. Rev., 2006, 106,2875-2911. Compounds are prepared using standard organic chemistrytechniques such as those described in, for example, March's AdvancedOrganic Chemistry, 6^(th) Edition, John Wiley and Sons, Inc. Alternativereaction conditions for the synthetic transformations described hereinmay be employed such as variation of solvent, reaction temperature,reaction time, as well as different chemical reagents and other reactionconditions. The starting materials are available from commercial sourcesor are readily prepared. Many functionalized indole and 2-oxindolecompounds are commercially available.

In some embodiments, the preparation of indole compounds begins with thesequence of steps shown in Scheme 1.

In some embodiments, Boc-protected 2-iodoanilines (I-1) are treated withTMS-acetylene using Sonogashira cross-coupling conditions to generatethe alkyne I-2 which, upon treatment with base then cyclizes to giveindoles of general structure I-3.

In other embodiments, the preparation of indole compounds begins withthe sequence of steps shown in Scheme II.

The Leimgruber-Batcho indole synthesis is described in Scheme II.Substituted 0-nitrotoluene II-1 can be reacted with dimethylformamidedimethyl acetal (DMFDMA) to provide the vinyl intermediate II-2.Reductive cyclization using, for example, nickel boride and hydrazinethen yields the indole of general structure II-3.

In other embodiments, the preparation of indole compounds begins withthe sequence of steps shown in Scheme III.

The Bartoli indole synthesis is shown in Scheme III and requires anortho-substituted nitrobenzene (III-1). Treatment of III-1 with a vinylmagnesium Grignard reagent results in an indole of general structureIII-2.

In some embodiments, 2-H Indoles are functionalized as shown in SchemeIV.

In some embodiments, treatment of 2-H Indoles of general structure IV-1or IV-2 with NCS or NBS in an inert solvent affords 2-chloro or bromoindoles of general structure IV-3 or IV-4.

In yet other embodiments, 2-oxindoles are used to prepare compoundsdescribed herein as shown in Scheme V.

In some embodiments, 2-oxindoles such as V-1 are treated with POCl₃ orPOBr₃ to yield the 2-chloro or 2-bromo derivatives V-2. In someembodiments, compound V-2 is then functionalized at C-3 of the indole tointroduce a 3-thioether group by reacting with an appropriatelysubstituted arylthiol in the presence of NCS to give compounds ofstructure V-3. In further embodiments, the 2-halo substituent is then beconverted to V-4 containing a 2-cyano substituent. In some embodiments,this transformation is performed with the use of organometallic reagentssuch as, for example, Zn(CN)₂ in the presence of a palladium catalystsuch as Pd₂(dba)₃ and ligand such as xantphos. Alternative CN sourcesmay be used such as CuCN at high temperature. Other ways of preparing2-cyanoindoles include the dehydration of the corresponding primaryamide. In some embodiments, introduction of a 2-cyclopropyl group isachieved by treating V-3 with cyclopropylboronic acid under Suzuki-typecouple conditions to yield V-5.

In some embodiments, indoles compounds described herein are prepared asshown in Scheme VI.

In some embodiments, the Fisher indole reaction using the hydrazine VI-1or VI-2 and the cyclopropylketone VI-3a is used to prepare 2-cyclopropylindoles of general structure VI-4 (Scheme VI). In some embodiments, the3-thio substituted 2-cyclopropyl indole VI-5 is prepared using thecyclopropylketone VI-3b.

N—H Indoles of general structure VII-1 may be further modified as shownin Scheme VII.

Treatment with a base such as NaH followed by alkylation with anelectrophile (for example BrCH₂CONR′R″ or BrCH₂CH₂CO₂tBu or ClCH₂Aryl)can then form compounds of general structure VII-2. Subsequent chemicalmodifications can then be made to the indole N-substituent usingstandard chemical transformations. Direct arylation or heteroarylationmay be achieved using Ullman-type conditions to generate VII-3.

In some embodiments, compounds described herein are synthesized asoutlined in the Examples.

Certain Terminology

Unless otherwise stated, the following terms used in this applicationhave the definitions given below. The use of the term “including” aswell as other forms, such as “include”, “includes,” and “included,” isnot limiting. The section headings used herein are for organizationalpurposes only and are not to be construed as limiting the subject matterdescribed.

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x). By way ofexample only, a group designated as “C₁-C₄” indicates that there are oneto four carbon atoms in the moiety, i.e. groups containing 1 carbonatom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way ofexample only, “C₁-C₄ alkyl” indicates that there are one to four carbonatoms in the alkyl group, i.e., the alkyl group is selected from amongmethyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, andt-butyl.

An “alkyl” group refers to an aliphatic hydrocarbon group. The alkylgroup is branched or straight chain. In some embodiments, the “alkyl”group has 1 to 10 carbon atoms, i.e. a C₁-C₁₀alkyl. Whenever it appearsherein, a numerical range such as “1 to 10” refers to each integer inthe given range; e.g., “1 to 10 carbon atoms” means that the alkyl groupconsist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up toand including 10 carbon atoms, although the present definition alsocovers the occurrence of the term “alkyl” where no numerical range isdesignated. In some embodiments, an alkyl is a C₁-C₆alkyl. In one aspectthe alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, or t-butyl. Typical alkyl groups include, but are in no waylimited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

An “alkylene” group refers refers to a divalent alkyl radical. Any ofthe above mentioned monovalent alkyl groups may be an alkylene byabstraction of a second hydrogen atom from the alkyl. In someembodiments, an alkelene is a C₁-C₆alkylene. In other embodiments, analkylene is a C₁-C₄alkylene. Typical alkylene groups include, but arenot limited to, —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂CH₂—, —CH₂CH(CH₃)—,—CH₂C(CH₃)₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and the like.

“Deuteroalkyl” refers to an alkyl group where 1 or more hydrogen atomsof an alkyl are replaced with deuterium.

The term “alkenyl” refers to a type of alkyl group in which at least onecarbon-carbon double bond is present. In one embodiment, an alkenylgroup has the formula —C(R)═CR₂, wherein R refers to the remainingportions of the alkenyl group, which may be the same or different. Insome embodiments, R is H or an alkyl. Non-limiting examples of analkenyl group include —CH═CH₂, —C(CH₃)═CH₂, —CH═CHCH₃, —C(CH₃)═CHCH₃,and —CH₂CH═CH₂.

The term “alkynyl” refers to a type of alkyl group in which at least onecarbon-carbon triple bond is present. In one embodiment, an alkenylgroup has the formula —C≡C—R, wherein R refers to the remaining portionsof the alkynyl group. In some embodiments, R is H or an alkyl.Non-limiting examples of an alkynyl group include —C≡CH,—C≡CCH₃—C≡CCH₂CH₃, —CH₂C≡CH.

An “alkoxy” group refers to a (alkyl)O— group, where alkyl is as definedherein.

The term “alkylamine” refers to the —N(alkyl)_(x)H_(y) group, where x is0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0.

The term “aromatic” refers to a planar ring having a delocalizedπ-electron system containing 4n+2π electrons, where n is an integer. Theterm “aromatic” includes both carbocyclic aryl (“aryl”, e.g., phenyl)and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups(e.g., pyridine). The term includes monocyclic or fused-ring polycyclic(i.e., rings which share adjacent pairs of carbon atoms) groups.

The term “carbocyclic” or “carbocycle” refers to a ring or ring systemwhere the atoms forming the backbone of the ring are all carbon atoms.The term thus distinguishes carbocyclic from “heterocyclic” rings or“heterocycles” in which the ring backbone contains at least one atomwhich is different from carbon. In some embodiments, at least one of thetwo rings of a bicyclic carbocycle is aromatic. In some embodiments,both rings of a bicyclic carbocycle are aromatic.

As used herein, the term “aryl” refers to an aromatic ring wherein eachof the atoms forming the ring is a carbon atom. In one aspect, aryl isphenyl or a naphthyl. In some embodiments, an aryl is a phenyl. In someembodiments, an aryl is a C₆-C₁₀aryl. Depending on the structure, anaryl group is a monoradical or a diradical (i.e., an arylene group).

The term “cycloalkyl” refers to a monocyclic or polycyclic aliphatic,non-aromatic radical, wherein each of the atoms forming the ring (i.e.skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls arespirocyclic or bridged compounds. In some embodiments, cycloalkyls areoptionally fused with an aromatic ring, and the point of attachment isat a carbon that is not an aromatic ring carbon atom. Cycloalkyl groupsinclude groups having from 3 to 10 ring atoms. In some embodiments,cycloalkyl groups are selected from among cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl,cyclooctyl, spiro[2.2]pentyl, norbornyl and bicycle[1.1.1]pentyl. Insome embodiments, a cycloalkyl is a C₃-C₆cycloalkyl.

The term “halo” or, alternatively, “halogen” or “halide” means fluoro,chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, orbromo.

The term “fluoroalkyl” refers to an alkyl in which one or more hydrogenatoms are replaced by a fluorine atom. In one aspect, a fluoralkyl is aC₁-C₆fluoroalkyl.

The term “heteroalkyl” refers to an alkyl group in which one or moreskeletal atoms of the alkyl are selected from an atom other than carbon,e.g., oxygen, nitrogen (e.g. —NH—, —N(alkyl)-, sulfur, or combinationsthereof. A heteroalkyl is attached to the rest of the molecule at acarbon atom of the heteroalkyl. In one aspect, a heteroalkyl is aC₁-C₆heteroalkyl.

The term “heterocycle” or “heterocyclic” refers to heteroaromatic rings(also known as heteroaryls) and heterocycloalkyl rings (also known asheteroalicyclic groups) containing one to four heteroatoms in thering(s), where each heteroatom in the ring(s) is selected from O, S andN, wherein each heterocyclic group has from 3 to 10 atoms in its ringsystem, and with the proviso that any ring does not contain two adjacentO or S atoms. Non-aromatic heterocyclic groups (also known asheterocycloalkyls) include rings having 3 to 10 atoms in its ring systemand aromatic heterocyclic groups include rings having 5 to 10 atoms inits ring system. The heterocyclic groups include benzo-fused ringsystems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl,tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl,morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl,azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl,oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl,pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl,dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl,dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl,imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl,3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl,isoindolin-1-onyl, isoindoline-1,3-dionyl,3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl,isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl,1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, andquinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. The foregoing groups are either C-attached (or C-linked)or N-attached where such is possible. For instance, a group derived frompyrrole includes both pyrrol-1-yl (N-attached) or pyrrol-3-yl(C-attached). Further, a group derived from imidazole includesimidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl,imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groupsinclude benzo-fused ring systems. Non-aromatic heterocycles areoptionally substituted with one or two oxo (═O) moieties, such aspyrrolidin-2-one. In some embodiments, at least one of the two rings ofa bicyclic heterocycle is aromatic. In some embodiments, both rings of abicyclic heterocycle are aromatic.

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to anaryl group that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groupsinclude monocyclic heteroaryls and bicyclic heteroaryls. Monocyclicheteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl,triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl,thiadiazolyl, and furazanyl. Monocyclic heteroaryls include indolizine,indole, benzofuran, benzothiophene, indazole, benzimidazole, purine,quinolizine, quinoline, isoquinoline, cinnoline, phthalazine,quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In someembodiments, a heteroaryl contains 0-4 N atoms in the ring. In someembodiments, a heteroaryl contains 1-4 N atoms in the ring. In someembodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 Satoms in the ring. In some embodiments, a heteroaryl contains 1-4 Natoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments,heteroaryl is a C₁-C₉heteroaryl. In some embodiments, monocyclicheteroaryl is a C₁-C₅heteroaryl. In some embodiments, monocyclicheteroaryl is a 5-membered or 6-membered heteroaryl. In someembodiments, bicyclic heteroaryl is a C₆-C₉heteroaryl.

A “heterocycloalkyl” or “heteroalicyclic” group refers to a cycloalkylgroup that includes at least one heteroatom selected from nitrogen,oxygen and sulfur. In some embodiments, a heterocycloalkyl is fused withan aryl or heteroaryl. In some embodiments, the heterocycloalkyl isoxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, piperidin-2-onyl,pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl,imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. The termheteroalicyclic also includes all ring forms of the carbohydrates,including but not limited to the monosaccharides, the disaccharides andthe oligosaccharides. In one aspect, a heterocycloalkyl is aC₂-C₁₀heterocycloalkyl. In another aspect, a heterocycloalkyl is aC₄-C₁₀heterocycloalkyl. In some embodiments, a heterocycloalkyl contains0-2 N atoms in the ring. In some embodiments, a heterocycloalkylcontains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure. In one aspect, when a group describedherein is a bond, the referenced group is absent thereby allowing a bondto be formed between the remaining identified groups.

The term “moiety” refers to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

The term “optionally substituted” or “substituted” means that thereferenced group is optionally substituted with one or more additionalgroup(s) individually and independently selected from halogen, —CN,—NH₂, —NH(alkyl), —N(alkyl)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂,—C(═O)NH(alkyl), —C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl),—S(═O)₂N(alkyl)₂, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy,fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio,arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone.In some other embodiments, optional substituents are independentlyselected from halogen, —CN, —NH₂, —NH(CH₃), —N(CH₃)₂, —OH, —CO₂H,—CO₂(C₁-C₄alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₄alkyl), —C(═O)N(C₁-C₄alkyl)₂,—S(═O)₂NH₂, —S(═O)₂NH(C₁-C₄alkyl), —S(═O)₂N(C₁-C₄alkyl)₂, C₁-C₄alkyl,C₃-C₆cycloalkyl, C₁-C₄fluoroalkyl, C₁-C₄heteroalkyl, C₁-C₄alkoxy,C₁-C₄fluoroalkoxy, —SC₁-C₄alkyl, —S(═O)C₁-C₄alkyl, and—S(═O)₂C₁-C₄alkyl. In some embodiments, optional substituents areindependently selected from halogen, —CN, —NH₂, —OH, —NH(CH₃), —N(CH₃)₂,—CH₃, —CH₂CH₃, —CF₃, —OCH₃, and —OCF₃. In some embodiments, substitutedgroups are substituted with one or two of the preceding groups. In someembodiments, an optional substituent on an aliphatic carbon atom(acyclic or cyclic) includes oxo (═O).

The term “acceptable” with respect to a formulation, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the subject being treated.

The term “modulate” as used herein, means to interact with a targeteither directly or indirectly so as to alter the activity of the target,including, by way of example only, to enhance the activity of thetarget, to inhibit the activity of the target, to limit the activity ofthe target, or to extend the activity of the target.

The term “modulator” as used herein, refers to a molecule that interactswith a target either directly or indirectly. The interactions include,but are not limited to, the interactions of an agonist, partial agonist,an inverse agonist, antagonist, degrader, or combinations thereof. Insome embodiments, a modulator is an antagonist. In some embodiments, amodulator is a degrader.

The terms “administer,” “administering”, “administration,” and the like,as used herein, refer to the methods that may be used to enable deliveryof compounds or compositions to the desired site of biological action.These methods include, but are not limited to oral routes, intraduodenalroutes, parenteral injection (including intravenous, subcutaneous,intraperitoneal, intramuscular, intravascular or infusion), topical andrectal administration. Those of skill in the art are familiar withadministration techniques that can be employed with the compounds andmethods described herein. In some embodiments, the compounds andcompositions described herein are administered orally.

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered, which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result includesreduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition comprising a compound as disclosed herein required toprovide a clinically significant decrease in disease symptoms. Anappropriate “effective” amount in any individual case is optionallydetermined using techniques, such as a dose escalation study.

The terms “enhance” or “enhancing,” as used herein, means to increase orprolong either in potency or duration a desired effect. Thus, in regardto enhancing the effect of therapeutic agents, the term “enhancing”refers to the ability to increase or prolong, either in potency orduration, the effect of other therapeutic agents on a system. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of another therapeutic agent in a desiredsystem.

The term “pharmaceutical combination” as used herein, means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound described herein, or a pharmaceuticallyacceptable salt thereof, and a co-agent, are both administered to apatient simultaneously in the form of a single entity or dosage. Theterm “non-fixed combination” means that the active ingredients, e.g. acompound described herein, or a pharmaceutically acceptable saltthereof, and a co-agent, are administered to a patient as separateentities either simultaneously, concurrently or sequentially with nospecific intervening time limits, wherein such administration provideseffective levels of the two compounds in the body of the patient. Thelatter also applies to cocktail therapy, e.g. the administration ofthree or more active ingredients.

The terms “kit” and “article of manufacture” are used as synonyms.

The term “subject” or “patient” encompasses mammals. Examples of mammalsinclude, but are not limited to, any member of the Mammalian class:humans, non-human primates such as chimpanzees, and other apes andmonkey species; farm animals such as cattle, horses, sheep, goats,swine; domestic animals such as rabbits, dogs, and cats; laboratoryanimals including rodents, such as rats, mice and guinea pigs, and thelike. In one aspect, the mammal is a human.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating at least one symptom of a diseaseor condition, preventing additional symptoms, inhibiting the disease orcondition, e.g., arresting the development of the disease or condition,relieving the disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically.

Pharmaceutical Compositions

In some embodiments, the compounds described herein are formulated intopharmaceutical compositions. Pharmaceutical compositions are formulatedin a conventional manner using one or more pharmaceutically acceptableinactive ingredients that facilitate processing of the active compoundsinto preparations that are used pharmaceutically. Proper formulation isdependent upon the route of administration chosen. A summary ofpharmaceutical compositions described herein is found, for example, inRemington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton,Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington'sPharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975;Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms,Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms andDrug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999),herein incorporated by reference for such disclosure.

In some embodiments, the compounds described herein are administeredeither alone or in combination with pharmaceutically acceptablecarriers, excipients or diluents, in a pharmaceutical composition.Administration of the compounds and compositions described herein can beeffected by any method that enables delivery of the compounds to thesite of action. These methods include, though are not limited todelivery via enteral routes (including oral, gastric or duodenal feedingtube, rectal suppository and rectal enema), parenteral routes (injectionor infusion, including intraarterial, intracardiac, intradermal,intraduodenal, intramedullary, intramuscular, intraosseous,intraperitoneal, intrathecal, intravascular, intravenous, intravitreal,epidural and subcutaneous), inhalational, transdermal, transmucosal,sublingual, buccal and topical (including epicutaneous, dermal, enema,eye drops, ear drops, intranasal, vaginal) administration, although themost suitable route may depend upon for example the condition anddisorder of the recipient. By way of example only, compounds describedherein can be administered locally to the area in need of treatment, byfor example, local infusion during surgery, topical application such ascreams or ointments, injection, catheter, or implant. The administrationcan also be by direct injection at the site of a diseased tissue ororgan.

In some embodiments, pharmaceutical compositions suitable for oraladministration are presented as discrete units such as capsules, cachetsor tablets each containing a predetermined amount of the activeingredient; as a powder or granules; as a solution or a suspension in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water-in-oil liquid emulsion. In some embodiments, theactive ingredient is presented as a bolus, electuary or paste.

Pharmaceutical compositions which can be used orally include tablets,push-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. Tablets maybe made by compression or molding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with binders, inert diluents, orlubricating, surface active or dispersing agents. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. In some embodiments, the tabletsare coated or scored and are formulated so as to provide slow orcontrolled release of the active ingredient therein. All formulationsfor oral administration should be in dosages suitable for suchadministration. The push-fit capsules can contain the active ingredientsin admixture with filler such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds may be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In some embodiments, stabilizers are added.Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or Dragee coatings for identification or to characterizedifferent combinations of active compound doses.

In some embodiments, pharmaceutical compositions are formulated forparenteral administration by injection, e.g., by bolus injection orcontinuous infusion. Formulations for injection may be presented in unitdosage form, e.g., in ampoules or in multi-dose containers, with anadded preservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. The compositions may be presented in unit-dose or multi-dosecontainers, for example sealed ampoules and vials, and may be stored inpowder form or in a freeze-dried (lyophilized) condition requiring onlythe addition of the sterile liquid carrier, for example, saline orsterile pyrogen-free water, immediately prior to use. Extemporaneousinjection solutions and suspensions may be prepared from sterilepowders, granules and tablets of the kind previously described.

Pharmaceutical compositions for parenteral administration includeaqueous and non-aqueous (oily) sterile injection solutions of the activecompounds which may contain antioxidants, buffers, bacteriostats andsolutes which render the formulation isotonic with the blood of theintended recipient; and aqueous and non-aqueous sterile suspensionswhich may include suspending agents and thickening agents. Suitablelipophilic solvents or vehicles include fatty oils such as sesame oil,or synthetic fatty acid esters, such as ethyl oleate or triglycerides,or liposomes. Aqueous injection suspensions may contain substances whichincrease the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may alsocontain suitable stabilizers or agents which increase the solubility ofthe compounds to allow for the preparation of highly concentratedsolutions.

Pharmaceutical compositions may also be formulated as a depotpreparation. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds may beformulated with suitable polymeric or hydrophobic materials (forexample, as an emulsion in an acceptable oil) or ion exchange resins, oras sparingly soluble derivatives, for example, as a sparingly solublesalt.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, pastilles, or gels formulated in conventionalmanner. Such compositions may comprise the active ingredient in aflavored basis such as sucrose and acacia or tragacanth.

Pharmaceutical compositions may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter, polyethyleneglycol, or other glycerides.

Pharmaceutical compositions may be administered topically, that is bynon-systemic administration. This includes the application of a compoundof the present invention externally to the epidermis or the buccalcavity and the instillation of such a compound into the ear, eye andnose, such that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral,intravenous, intraperitoneal and intramuscular administration.

Pharmaceutical compositions suitable for topical administration includeliquid or semi-liquid preparations suitable for penetration through theskin to the site of inflammation such as gels, liniments, lotions,creams, ointments or pastes, and drops suitable for administration tothe eye, ear or nose. The active ingredient may comprise, for topicaladministration, from 0.001% to 10% w/w, for instance from 1% to 2% byweight of the formulation.

Pharmaceutical compositions for administration by inhalation areconveniently delivered from an insufflator, nebulizer pressurized packsor other convenient means of delivering an aerosol spray. Pressurizedpacks may comprise a suitable propellant such asdichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. Alternatively, foradministration by inhalation or insufflation, pharmaceuticalpreparations may take the form of a dry powder composition, for examplea powder mix of the compound and a suitable powder base such as lactoseor starch. The powder composition may be presented in unit dosage form,in for example, capsules, cartridges, gelatin or blister packs fromwhich the powder may be administered with the aid of an inhalator orinsufflator.

It should be understood that in addition to the ingredients particularlymentioned above, the compounds and compositions described herein mayinclude other agents conventional in the art having regard to the typeof formulation in question, for example those suitable for oraladministration may include flavoring agents.

Methods of Dosing and Treatment Regimens

In one embodiment, the compounds described herein, or a pharmaceuticallyacceptable salt thereof, are used in the preparation of medicaments forthe treatment of diseases or conditions in a mammal that would benefitfrom inhibition or reduction of autotaxin activity. Methods for treatingany of the diseases or conditions described herein in a mammal in needof such treatment, involves administration of pharmaceuticalcompositions that include at least one compound described herein or apharmaceutically acceptable salt, active metabolite, prodrug, orpharmaceutically acceptable solvate thereof, in therapeuticallyeffective amounts to said mammal.

In certain embodiments, the compositions containing the compound(s)described herein are administered for prophylactic and/or therapeutictreatments. In certain therapeutic applications, the compositions areadministered to a patient already suffering from a disease or condition,in an amount sufficient to cure or at least partially arrest at leastone of the symptoms of the disease or condition. Amounts effective forthis use depend on the severity and course of the disease or condition,previous therapy, the patient's health status, weight, and response tothe drugs, and the judgment of the treating physician. Therapeuticallyeffective amounts are optionally determined by methods including, butnot limited to, a dose escalation and/or dose ranging clinical trial.

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. When used in patients, effectiveamounts for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingphysician. In one aspect, prophylactic treatments include administeringto a mammal, who previously experienced at least one symptom of thedisease being treated and is currently in remission, a pharmaceuticalcomposition comprising a compound described herein, or apharmaceutically acceptable salt thereof, in order to prevent a returnof the symptoms of the disease or condition.

In certain embodiments wherein the patient's condition does not improve,upon the doctor's discretion the administration of the compounds areadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

In certain embodiments wherein a patient's status does improve, the doseof drug being administered is temporarily reduced or temporarilysuspended for a certain length of time (i.e., a “drug holiday”). Inspecific embodiments, the length of the drug holiday is between 2 daysand 1 year, including by way of example only, 2 days, 3 days, 4 days, 5days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, ormore than 28 days. The dose reduction during a drug holiday is, by wayof example only, by 10%-100%, including by way of example only 10%, 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, and 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, in specificembodiments, the dosage or the frequency of administration, or both, isreduced, as a function of the symptoms, to a level at which the improveddisease, disorder or condition is retained. In certain embodiments,however, the patient requires intermittent treatment on a long-termbasis upon any recurrence of symptoms.

The amount of a given agent that corresponds to such an amount variesdepending upon factors such as the particular compound, diseasecondition and its severity, the identity (e.g., weight, sex) of thesubject or host in need of treatment, but nevertheless is determinedaccording to the particular circumstances surrounding the case,including, e.g., the specific agent being administered, the route ofadministration, the condition being treated, and the subject or hostbeing treated.

In general, however, doses employed for adult human treatment aretypically in the range of 0.01 mg-5000 mg per day. In one aspect, dosesemployed for adult human treatment are from about 1 mg to about 1000 mgper day. In one embodiment, the desired dose is conveniently presentedin a single dose or in divided doses administered simultaneously or atappropriate intervals, for example as two, three, four or more sub-dosesper day.

In one embodiment, the daily dosages appropriate for the compounddescribed herein, or a pharmaceutically acceptable salt thereof, arefrom about 0.01 to about 50 mg/kg per body weight. In some embodiments,the daily dosage or the amount of active in the dosage form are lower orhigher than the ranges indicated herein, based on a number of variablesin regard to an individual treatment regime. In various embodiments, thedaily and unit dosages are altered depending on a number of variablesincluding, but not limited to, the activity of the compound used, thedisease or condition to be treated, the mode of administration, therequirements of the individual subject, the severity of the disease orcondition being treated, and the judgment of the practitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens aredetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ and the ED₅₀. The dose ratio between the toxic andtherapeutic effects is the therapeutic index and it is expressed as theratio between LD₅₀ and ED₅₀. In certain embodiments, the data obtainedfrom cell culture assays and animal studies are used in formulating thetherapeutically effective daily dosage range and/or the therapeuticallyeffective unit dosage amount for use in mammals, including humans. Insome embodiments, the daily dosage amount of the compounds describedherein lies within a range of circulating concentrations that includethe ED₅₀ with minimal toxicity. In certain embodiments, the daily dosagerange and/or the unit dosage amount varies within this range dependingupon the dosage form employed and the route of administration utilized.

In some embodiments, liver toxicity can be assessed in suitable in vivoassays. In some embodiments, liver toxicity is assessed by monitoringany increases in the levels of liver markers ALT, AST, AlkP andbilirubin. For example, in a suitable dog liver toxicity study, Compound(1-34) exhibited undesired elevated liver markers whereas Compound(1-13) did not exhibit the same effects. In some embodiments, noincreases in liver markers ALT, AST, AlkP and bilirubin were observedfor Compound (1-13) when dosed at 100 mpk for 5 days.

In any of the aforementioned aspects are further embodiments in whichthe effective amount of the compound described herein, or apharmaceutically acceptable salt thereof, is: (a) systemicallyadministered to the mammal; and/or (b) administered orally to themammal; and/or (c) intravenously administered to the mammal; and/or (d)administered by injection to the mammal; and/or (e) administeredtopically to the mammal; and/or (f) administered non-systemically orlocally to the mammal.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredonce a day; or (ii) the compound is administered to the mammal multipletimes over the span of one day.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredcontinuously or intermittently: as in a single dose; (ii) the timebetween multiple administrations is every 6 hours; (iii) the compound isadministered to the mammal every 8 hours; (iv) the compound isadministered to the mammal every 12 hours; (v) the compound isadministered to the mammal every 24 hours. In further or alternativeembodiments, the method comprises a drug holiday, wherein theadministration of the compound is temporarily suspended or the dose ofthe compound being administered is temporarily reduced; at the end ofthe drug holiday, dosing of the compound is resumed. In one embodiment,the length of the drug holiday varies from 2 days to 1 year.

In certain instances, it is appropriate to administer at least onecompound described herein, or a pharmaceutically acceptable saltthereof, in combination with one or more other therapeutic agents. Incertain embodiments, the pharmaceutical composition further comprisesone or more anti-cancer agents.

In one embodiment, the therapeutic effectiveness of one of the compoundsdescribed herein is enhanced by administration of an adjuvant (i.e., byitself the adjuvant has minimal therapeutic benefit, but in combinationwith another therapeutic agent, the overall therapeutic benefit to thepatient is enhanced). Or, in some embodiments, the benefit experiencedby a patient is increased by administering one of the compoundsdescribed herein with another agent (which also includes a therapeuticregimen) that also has therapeutic benefit.

In one specific embodiment, a compound described herein, or apharmaceutically acceptable salt thereof, is co-administered with asecond therapeutic agent, wherein the compound described herein, or apharmaceutically acceptable salt thereof, and the second therapeuticagent modulate different aspects of the disease, disorder or conditionbeing treated, thereby providing a greater overall benefit thanadministration of either therapeutic agent alone.

In any case, regardless of the disease, disorder or condition beingtreated, the overall benefit experienced by the patient is simply beadditive of the two therapeutic agents or the patient experiences asynergistic benefit.

In certain embodiments, different therapeutically-effective dosages ofthe compounds disclosed herein will be utilized in formulatingpharmaceutical composition and/or in treatment regimens when thecompounds disclosed herein are administered in combination with one ormore additional agent, such as an additional therapeutically effectivedrug, an adjuvant or the like. Therapeutically-effective dosages ofdrugs and other agents for use in combination treatment regimens isoptionally determined by means similar to those set forth hereinabovefor the actives themselves. Furthermore, the methods ofprevention/treatment described herein encompasses the use of metronomicdosing, i.e., providing more frequent, lower doses in order to minimizetoxic side effects. In some embodiments, a combination treatment regimenencompasses treatment regimens in which administration of a compounddescribed herein, or a pharmaceutically acceptable salt thereof, isinitiated prior to, during, or after treatment with a second agentdescribed herein, and continues until any time during treatment with thesecond agent or after termination of treatment with the second agent. Italso includes treatments in which a compound described herein, or apharmaceutically acceptable salt thereof, and the second agent beingused in combination are administered simultaneously or at differenttimes and/or at decreasing or increasing intervals during the treatmentperiod. Combination treatment further includes periodic treatments thatstart and stop at various times to assist with the clinical managementof the patient.

It is understood that the dosage regimen to treat, prevent, orameliorate the condition(s) for which relief is sought, is modified inaccordance with a variety of factors (e.g. the disease, disorder orcondition from which the subject suffers; the age, weight, sex, diet,and medical condition of the subject). Thus, in some instances, thedosage regimen actually employed varies and, in some embodiments,deviates from the dosage regimens set forth herein.

For combination therapies described herein, dosages of theco-administered compounds vary depending on the type of co-drugemployed, on the specific drug employed, on the disease or conditionbeing treated and so forth. In additional embodiments, whenco-administered with one or more other therapeutic agents, the compoundprovided herein is administered either simultaneously with the one ormore other therapeutic agents, or sequentially.

In combination therapies, the multiple therapeutic agents (one of whichis one of the compounds described herein) are administered in any orderor even simultaneously. If administration is simultaneous, the multipletherapeutic agents are, by way of example only, provided in a single,unified form, or in multiple forms (e.g., as a single pill or as twoseparate pills).

The compounds described herein, or a pharmaceutically acceptable saltthereof, as well as combination therapies, are administered before,during or after the occurrence of a disease or condition, and the timingof administering the composition containing a compound varies. Thus, inone embodiment, the compounds described herein are used as aprophylactic and are administered continuously to subjects with apropensity to develop conditions or diseases in order to prevent theoccurrence of the disease or condition. In another embodiment, thecompounds and compositions are administered to a subject during or assoon as possible after the onset of the symptoms. In specificembodiments, a compound described herein is administered as soon as ispracticable after the onset of a disease or condition is detected orsuspected, and for a length of time necessary for the treatment of thedisease. In some embodiments, the length required for treatment varies,and the treatment length is adjusted to suit the specific needs of eachsubject. For example, in specific embodiments, a compound describedherein or a formulation containing the compound is administered for atleast 2 weeks, about 1 month to about 5 years.

In some embodiments, a compound described herein, or a pharmaceuticallyacceptable salt thereof, is administered in combination withchemotherapy, hormone blocking therapy, radiation therapy, monoclonalantibodies, or combinations thereof

Chemotherapy includes the use of anti-cancer agents.

EXAMPLES

The following examples are provided for illustrative purposes only andnot to limit the scope of the claims provided herein.

Synthesis of ethyl 2-fluoro-3-mercaptobenzoate (Intermediate A)

Step 1: Synthesis of ethyl 3-bromo-2-fluorobenzoate (2)

To a stirred solution of 3-bromo-2-fluorobenzoic acid 1 (25.0 g, 114.15mmol) in ethanol (400 mL) was added conc. H₂SO₄ (3 mL) at RT and stirredat reflux temperature for 24 h. The reaction was monitored by LC-MS;after completion of the reaction, the reaction mixture was concentratedto obtain the residue. The residue was diluted with EtOAc (500 mL),washed with water (300 mL), brine (300 mL), dried over Na₂SO₄, filteredand concentrated under reduced pressure to afford compound 2 (26.0 g,92%) as a light yellow liquid. ¹H NMR (400 MHz, CDCl₃): δ 7.88-7.84 (m,1H), 7.72-7.69 (m, 1H), 7.08-7.04 (m, 1H), 4.39 (q, J=7.2 Hz, 2H), 1.39(t, J=7.2 Hz, 3H).

Step 2: Synthesis of ethyl 2-fluoro-3-((4-methoxybenzyl)thio)benzoate(3)

1,4-dioxane (250 mL) was degassed by purging with N₂ gas for 30 min andto this, were added a solution of compound 2 (13.2 g, 53.4 mmol) in1,4-dioxane (50 mL; degassed), (4-methoxyphenyl)methanethiol (PMBSH)(8.2 g, 53.4 mmol), xantphos (1.54 g, 2.66 mmol), diisopropyl ethylamine (19.6 mL, 106.8 mmol) and Pd₂(dba)₃ (1.22 g, 1.33 mmol) at RT. Thereaction mixture was heated to 90° C. and stirred for 2 h. The reactionwas monitored by TLC; after completion of the reaction, the reactionmixture was diluted with hexane (450 mL) and stirred at RT for 15 min.The resultant solution was filtered through celite and washed withhexane (100 mL). The filtrate was washed water (250 mL) dried overNa₂SO₄, filtered and concentrated under reduced pressure to obtain thecrude. This was purified by silica gel column chromatography using 3-4%EtOAc/Hexanes to afford compound 3 (15 g, 88%) as pale yellow solid. ¹HNMR (500 MHz, CDCl₃): δ 7.78-7.74 (m, 1H), 7.43-7.39 (m, 1H), 7.19 (d,J=8.0 Hz, 2H), 7.07-7.04 (m, 1H), 6.80 (d, J=8.0 Hz, 2H), 4.41 (q, J=7.2Hz, 2H), 4.08 (s, 2H), 3.78 (s, 3H), 1.41 (t, J=7.2 Hz, 3H). LC-MS(ESI): 89.7%; m/z 318.9 (M−H⁺); (column: X Select CSH C-18, 50×3.0 mm,3.5 μm); RT 4.22 min; 5 mM NH₄OAc: ACN; 0.8 mL/min).

Step 3: Synthesis of ethyl 2-fluoro-3-mercaptobenzoate (A)

A stirred solution of compound 3 (30.0 g, 93.75 mmol) in TFA (54.5 mL)was heated to 80° C. and stirred for 12 h under inert atmosphere. Thereaction was monitored by TLC; after completion of the reaction, thevolatiles were removed under reduced pressure. The residue was dissolvedin ice-cold water (100 mL), basified with solid sodium bicarbonate andextracted with EtOAc (2×200 mL). The combined organic extracts weredried over Na₂SO₄, filtered and concentrated under reduced pressure toobtain the crude. This was purified by silica gel column chromatographyusing 3% EtOAc/Hexanes to afford compound A (11.7 g, 62%) as a palebrown syrup. ¹H NMR (500 MHz, CDCl₃): δ 7.70-7.66 (m, 1H), 7.48-7.44 (m,1H), 7.08-7.04 (m, 1H), 4.20 (q, J=7.5 Hz, 2H), 3.67 (s, 1H), 1.40 (t,J=7.5 Hz, 3H); LC-MS (ESI): 91.8%; m/z 199.0 (M−H⁺); (column: X SelectCSH C-18, 50×3.0 mm, 3.5 μm); RT 2.60 min; 5 mM NH₄OAc: ACN; 0.8mL/min).

Synthesis of 4-bromo-1-propyl-1H-pyrazole (Intermediate B)

A solution of 4-bromo-1H-pyrazole (25.0 g, 170.10 mmol) in THF (100 mL)was added drop wise to NaH (10.2 g, 255.0 mmol; 60% in oil) in THF (200mL) at 0° C. under inert atmosphere and stirred for 30 min. The reactionmixture was then warmed to rt and stirring was continued for additional45 min. To this, iodopropane (31.8 g, 204.12 mmol) was added at 0° C.;warmed to rt and stirred for 12 h. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture was quenched withwater (40 mL) and extracted with EtOAc (3×50 mL). The combined organicextracts were dried over Na₂SO₄, filtered and concentrated under reducedpressure to obtain the crude. This was purified by silica gel columnchromatography using 2-5% EtOAc/Hexanes to afford intermediate B(4-bromo-1-propyl-1H-pyrazole; 27.3 g, 86%) as a colorless oil. ¹H NMR(400 MHz, CDCl₃): δ 7.44 (s, 1H), 7.38 (s, 1H), 4.04 (t, J=7.2 Hz, 2H),1.90-1.82 (m, 2H), 0.92 (t, J=7.2 Hz, 3H); MS (ESI): m/z 189 (M+H⁺).

Synthesis of 4-bromo-1-methyl-1H-pyrazole (Intermediate C)

Following the procedure for Intermediate B but using EtI in place ofiodopropane, Intermediate C was prepared as a pale yellow liquid. ¹H NMR(500 MHz, CDCl₃): δ 7.45 (s, 1H), 7.38 (s, 1H), 3.79 (s, 3H).

Synthesis of 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole(Intermediate D)

Following the procedure for Intermediate B but using SEM chloride inplace of iodopropane, Intermediate D was prepared as a yellow liquid. ¹HNMR (500 MHz, DMSO-d₆): δ 8.15 (s, 1H), 7.63 (s, 1H), 5.38 (s, 2H), 3.52(t, J=8.5 Hz, 2H), 0.82 (t, J=7.5 Hz, 2H), 0.04 (s, 9H).

Synthesis of 4-bromo-1-(ethyl-d₅)-1H-pyrazole (Intermediate E)

Following the procedure for Intermediate B but using ethyl iodide-d₅ inplace of iodopropane, Intermediate E was prepared as a colorless oil. ¹HNMR (500 MHz, CDCl₃): δ 7.44 (s, 1H), 7.40 (s, 1H).

Synthesis of 4-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazole (IntermediateF)

Following the procedure for Intermediate B but using1,1,1-trifluoro-2-iodoethane in place of iodopropane and Cs₂CO₃/DMF inplace of NaH/THF, Intermediate F was prepared as a colorless oil. ¹H NMR(400 MHz, CDCl₃): δ 7.55 (s, 1H), 7.54 (s, 1H), 4.67 (q, 2H).

Example 1 Synthesis of3-((2,6-dichloro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoicacid (Compound 1-1)

Step 1: Synthesis of 2,6-dichloro-1H-indole (2)

To a stirred solution of 6-chloroindolin-2-one 1 (500 mg, 2.99 mmol) intoluene (25 mL) under inert atmosphere were added N,N-dimethylaniline(362 mg, 2.99 mmol) and POCl₃ (918 g, 5.98 mmol) at RT; heated to 110°C. and stirred for 1 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was quenched with 10%aq. NaHCO₃ solution (30 mL) and extracted with EtOAc (2×30 mL). Thecombined organic extracts were dried over Na₂SO₄, filtered andconcentrated under reduced pressure to obtain the crude. This waspurified by silica gel column chromatography using 5% EtOAc/Hexanes toafford compound 2 (350 mg, 63%) as an off-white solid. ¹H NMR (400 MHz,CDCl₃): δ 8.09 (br s, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.28 (s, 1H), 7.09(d, J=8.4 Hz, 1H), 6.39 (s, 1H); MS (ESI): m/z 184 (M−H⁺)

Step 2: Synthesis of 2,6-dichloro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indole(3)

To a stirred solution of compound 2 (350 mg, 1.89 mmol) in toluene (10mL) under inert atmosphere were added 4-bromo-1-propyl-1H-pyrazole(Intermediate B; 422 mg, 2.27 mmol), potassium phosphate (1 g, 4.72mmol), N,N′-dimethylethylene diamine (66.7 mg, 0.75 mmol) and CuI (36mg, 0.18 mmol) at RT; heated to 120° C. and stirred for 12 h in a sealedtube. The reaction was monitored by TLC; after completion of thereaction, the volatiles were removed under reduced pressure to obtainthe crude. This was purified by silica gel column chromatography using5-7% EtOAc/Hexanes to afford compound 3 (200 mg, 36%) as colorless oil.¹H NMR (500 MHz, CDCl₃): δ 7.63 (s, 1H), 7.59 (s, 1H), 7.44 (d, J=9.0Hz, 1H), 7.14 (s, 1H), 7.11 (d, J=9.0 Hz, 1H), 6.55 (s, 1H), 4.18 (t,J=7.0 Hz, 2H), 2.02-1.97 (m, 2H), 0.98 (t, J=7.5 Hz, 3H); LC-MS (ESI):59.4%; m/z 294.2 (M+H⁺); (column: X Select C-18, 50×3.0 mm, 3.5 μm); RT4.66 min; 5 mM NH₄OAc: ACN; 0.8 mL/min).

Step 3: Synthesis of ethyl3-((2,6-dichloro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoate (4)

To a stirred solution of ethyl 3-mercaptobenzoate (124.9 mg, 0.68 mmol)in CH₂Cl₂ (20 mL) under inert atmosphere was added NCS (109 mg, 0.81mmol) at 0° C.; warmed to RT and stirred for 1 h. To this, compound 3(200 mg, 0.68 mmol) was added at 0° C.; warmed to RT and stirred for 12h. The reaction was monitored by TLC; after completion of the reaction,the reaction mixture was diluted with water (25 mL) and extracted withCH₂Cl₂ (3×25 mL). The combined organic extracts were dried over Na₂SO₄,filtered and concentrated under reduced pressure to obtain the crude.This was purified by preparative HPLC to afford compound 4 (15 mg, 5%)as colorless oil. ¹H NMR (500 MHz, CDCl₃): δ 7.90 (s, 1H), 7.79-7.77 (m,1H), 7.69 (s, 1H), 7.66 (s, 1H), 7.48 (d, J=9.0 Hz, 1H), 7.26-7.22 (m,3H), 7.16 (d, J=9.0 Hz, 1H), 4.32 (q, J=7.5 Hz, 2H), 4.20 (t, J=7.0 Hz,2H), 2.02-1.98 (m, 2H), 1.37-1.34 (t, J=7.5 Hz, 3H), 1.01 (t, J=7.0 Hz,3H); LC-MS (ESI): 92.7%; m/z 475.8 (M+H⁺); (column: X Select C-18,50×3.0 mm, 3.5 μm); RT 5.03 min; 5 mM NH₄OAc: ACN; 0.8 mL/min).

Step 4: Synthesis of3-((2,6-dichloro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic acid

To a stirred solution of compound 4 (15 mg, 0.031 mmol) in THF:H₂O (1:1,5 mL) under inert atmosphere was added LiOH.H₂O (5.3 mg, 0.12 mmol) at0° C.; warmed to RT and stirred for 12 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed underreduced pressure. The residue was diluted with water (20 mL), acidifiedwith citric acid and extracted with CH₂Cl₂ (2×20 mL). The combinedorganic extracts were dried over Na₂SO₄, filtered and concentrated underreduced pressure to afford the title compound 1-1 (10 mg, 71%) as anoff-white solid. ¹H NMR (400 MHz, CD₃OD): δ 8.12 (s, 1H), 7.78-7.75 (m,3H), 7.49 (d, J=8.4 Hz, 1H), 7.32-7.31 (m, 2H), 7.22-7.18 (m, 2H), 4.24(t, J=7.2 Hz, 2H), 2.02-1.93 (m, 2H), 0.98 (t, J=7.2 Hz, 3H); MS (ESI):m/z 446.3 (M⁺); HPLC: 98.8%; (column: Acquity BEH C-18 (50×2.1 mm,1.7μ); RT 2.94 min; ACN: 0.025% TFA (aq); 0.5 mL/min.

Example 2 Synthesis of3-((6-chloro-2-cyano-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoicacid (Compound 1-3)

Step 1: Synthesis of 6-chloro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indole (2)

To a stirred solution of 6-chloro-1H-indole 1 (1.0 g, 6.62 mmol) intoluene (25 mL) under inert atmosphere were added N,N′-dimethylethylenediamine (233 mg, 2.64 mmol), potassium phosphate (3.50 g, 16.55 mmol)and 4-bromo-1-propyl-1H-pyrazole (Intermediate B; 1.23 g, 6.62 mmol) atRT and then degassed under argon for 15 min. To this, CuI (126 mg, 0.66mmol) was added and sealed the tube. The reaction mixture was heated to140° C. and stirred for 12 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was filtered and thefiltrate was concentrated under reduced pressure to obtain the crude.This was purified by silica gel column chromatography using 10-15%EtOAc/Hexanes to afford compound 2 (1.5 g, 88%) as yellow oil. ¹H NMR(500 MHz, CDCl₃): δ 7.68 (s, 1H), 7.62 (s, 1H), 7.55 (d, J=10.0 Hz, 1H),7.35 (s, 1H), 7.17 (d, J=3.5 Hz, 1H), 7.11 (d, J=10.0 Hz, 1H), 6.59 (d,J=3.5 Hz, 1H), 4.17 (t, J=7.5 Hz, 2H), 2.00-1.96 (m, 2H), 1.00 (t, J=7.5Hz, 3H); LC-MS (ESI): 93.3%; m/z 260.2 (M+H⁺); (column: X Select CSHC-18, 50×3.0 mm, 3.5 μm); RT 4.04 min; 5 mM NH₄OAc: ACN; 0.8 mL/min).

Step 2: Synthesis of ethyl3-((6-chloro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio) benzoate(3)

To a stirred solution of ethyl 3-mercaptobenzoate (372 mg, 2.03 mmol) inCH₂Cl₂ (20 mL) under inert atmosphere was added NCS (271 mg, 2.03 mmol)at 0° C.; warmed to RT and stirred for 45 min. To this, compound 2 (500mg, 1.93 mmol) was added at 0° C.; warmed to RT and stirred for 12 h.The reaction was monitored by TLC; after completion of the reaction, thereaction mixture was diluted with water (40 mL) and extracted withCH₂Cl₂ (3×20 mL). The combined organic extracts were dried over Na₂SO₄,filtered and concentrated under reduced pressure to obtain the crude.This was purified by silica gel column chromatography using 10-15%EtOAc/Hexanes to afford compound 3 (700 mg, 83%) as a yellow oil. ¹H NMR(400 MHz, CDCl₃): δ 7.89 (s, 1H), 7.76-7.74 (m, 1H), 7.72 (s, 1H), 7.68(s, 1H), 7.49-7.47 (m, 2H), 7.40 (s, 1H), 7.24-7.23 (m, 2H), 7.15 (d,J=8.4 Hz, 1H), 4.32 (q, J=7.2 Hz, 2H), 4.18 (t, J=7.2 Hz, 2H), 2.01-1.96(m, 2H), 1.34 (t, J=7.2 Hz, 3H), 1.00 (t, J=7.2 Hz, 3H); LC-MS (ESI):72.2%; m/z 440.4 (M+H⁺); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm);RT 4.87 min; 5 mM NH₄OAc: ACN; 0.8 mL/min).

Step 3: Synthesis of ethyl3-((2-bromo-6-chloro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoate (4)

To a stirred solution of compound 3 (100 mg, 0.22 mmol) in CCl₄ (10 mL)was added NBS (44.85 mg, 0.25 mmol) at RT under inert atmosphere andstirred for 12 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was diluted with water (20 mL) andextracted with CH₂Cl₂ (3×20 mL). The combined organic extracts weredried over sodium sulphate, filtered and concentrated under reducedpressure to obtain the crude. This was purified by silica gel columnchromatography using 10-15% EtOAc/Hexanes to afford compound 4 (55 mg,47%) as an off-white solid. ¹H NMR (500 MHz, CDCl₃): δ 7.90 (s, 1H),7.78-7.77 (m, 1H), 7.68 (s, 1H), 7.66 (s, 1H), 7.49 (d, J=8.5 Hz, 1H),7.25-7.24 (m, 2H), 7.20 (s, 1H), 7.14 (d, J=8.5 Hz, 1H), 4.35 (q, J=7.0Hz, 2H), 4.20 (t, J=7.5 Hz, 2H), 2.03-1.98 (m, 2H), 1.35 (t, J=7.0 Hz,3H), 1.01 (t, J=7.5 Hz, 3H); LC-MS (ESI): 93.3%; m/z 520.8 (M⁺+2);(column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 5.02 min; 5 mMNH₄OAc: ACN; 0.8 mL/min).

Step 4: Synthesis of ethyl3-((6-chloro-2-cyano-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl) thio)benzoate (5)

To a stirred solution of compound 4 (200 mg, 0.38 mmol) in DMA (20 mL)under inert atmosphere were added zinc powder (5.02 mg, 0.07 mmol),ZnCN₂ (67.8 mg, 0.58 mmol), xantphos (89.5 mg, 0.15 mmol), Pd₂(dba)₃(70.85 mg, 0.07 mmol) at RT; heated to 120° C. under microwave for 30min. The reaction was monitored by TLC; after completion of thereaction, the reaction mixture was diluted with water (20 mL) andextracted with CH₂Cl₂ (3×20 mL). The combined organic extracts weredried over Na₂SO₄, filtered and concentrated under reduced pressure toobtain the crude. This was purified by silica gel column chromatographyusing 10-15% EtOAc/Hexanes to afford compound 5 (60 mg, 33%) as anoff-white solid. ¹H NMR (500 MHz, CDCl₃): δ 7.99 (s, 1H), 7.87 (d, J=7.5Hz, 1H), 7.78 (s, 2H), 7.54 (d, J=8.5 Hz, 1H), 7.42-7.27 (m, 3H),7.24-7.22 (m, 1H), 4.36 (q, J=7.0 Hz, 2H), 4.21 (t, J=7.5 Hz, 2H),2.02-1.98 (m, 2H), 1.36 (t, J=7.0 Hz, 3H), 1.01 (t, J=7.5 Hz, 3H); LC-MS(ESI): 92.5%; m/z 465 (M+H⁺); (column: X Select CSH C-18, 50×3.0 mm, 3.5μm); RT 4.92 min; 5 mM NH₄OAc: ACN; 0.8 mL/min).

Step 5: Synthesis of3-((6-chloro-2-cyano-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl) thio)benzoic acid

To a stirred solution of compound 5 (60 mg, 0.12 mmol) in THF:MeOH:H₂O(3:1:1, 5 mL) under inert atmosphere was added LiOH.H₂O (16.3 mg, 0.38mmol) at 0° C.; warmed to RT and stirred for 4 h. The reaction wasmonitored by TLC; after completion of the reaction, the volatiles wereremoved under reduced pressure. The residue was diluted with water (15mL), acidified with citric acid to pH ˜2.0. The obtained solid wasfiltered and dried under reduced pressure to afford the title compound1-3 (20 mg, 35%) as an off-white solid. ¹H NMR (400 MHz, CD₃OD): δ 8.23(s, 1H), 7.88 (s, 1H), 7.87 (s, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.57 (d,J=8.4 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.38-7.32 (m, 2H), 7.27 (d, J=8.4Hz, 1H), 4.25 (t, J=7.2 Hz, 2H), 2.02-1.93 (m, 2H), 0.98 (t, J=7.2 Hz,3H); LC-MS (ESI): 96.4%; m/z 435.4 (M−H⁺); (column: X Select CSH C-18,50×3.0 mm, 3.5 μm); RT 3.19 min; 5 mM NH₄OAc: ACN; 0.8 mL/min); HPLC:94.6%; (column: Acquity BEH C-18 (50×2.1 mm, 1.7μ); RT 2.78 min; ACN:0.025% TFA (aq); 0.5 mL/min.

Example 3 Synthesis of3-((6-chloro-2-cyclopropyl-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoicacid (Compound 1-4)

Step 1: Synthesis of ethyl3-((6-chloro-2-cyclopropyl-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoate(2)

To a stirred solution of ethyl3-((2-bromo-6-chloro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoate1 (Example 2, Step 3; 100 mg, 0.19 mmol) in DME (20 mL) under inertatmosphere were added cyclopropyl boronic acid (16.6 mg, 0.19 mmol),KOAc (56.8 mg, 0.58 mmol) at RT and degassed for 15 min. To this, wasadded Pd(dppf)Cl₂ (28.3 mg, 0.038 mmol), heated to 85° C. and stirredfor 7 h. The reaction was monitored by TLC; after completion of thereaction, the reaction mixture was diluted with water (20 mL) andextracted with CH₂Cl₂ (3×20 mL). The combined organic extracts weredried over Na₂SO₄, filtered and concentrated under reduced pressure toobtain the crude. The crude was purified by silica gel columnchromatography using 8-10% EtOAc/Hexanes to afford 43 mg of compound 2with 51% purity. The impure material was further purified by preparativeHPLC to afford pure compound 2 (25 mg, 27%) as a colorless oil. ¹H NMR(500 MHz, CDCl₃): δ 7.83 (s, 1H), 7.74 (d, J=7.5 Hz, 1H), 7.69 (s, 1H),7.65 (s, 1H), 7.41 (d, J=8.5 Hz, 1H), 7.26-7.22 (m, 2H), 7.14-7.08 (m,2H), 4.34 (q, J=7.5 Hz, 2H), 4.21 (t, J=7.0 Hz, 2H), 2.03-1.98 (m, 2H),1.76-1.75 (m, 1H), 1.05-1.01 (m, 2H), 1.36 (t, J=7.5 Hz, 3H), 1.00 (t,J=7.0 Hz, 3H), 0.87-0.84 (m, 2H); LC-MS (ESI): 89.7%; m/z 480.5 (M+H⁺);(column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.83 min; 5 mMNH₄OAc: ACN; 0.8 mL/min).

Step 2: Synthesis of3-((6-chloro-2-cyclopropyl-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoicacid

To a stirred solution of compound 2 (25 mg, 0.05 mmol) in THF:H₂O (1:1,5 mL) under inert atmosphere was added LiOH.H₂O (6.5 mg, 0.15 mmol) at0° C.; warmed to RT and stirred for 12 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed underreduced pressure. The residue was diluted with water (15 mL), acidifiedwith citric acid and extracted with EtOAc (2×20 mL). The combinedorganic extracts were dried over Na₂SO₄, filtered and concentrated underreduced pressure to obtain the crude. The crude was triturated withn-pentane (2×5 mL) to afford the title compound 1-4 (10 mg, 43%) as anoff-white solid. ¹H NMR (400 MHz, CD₃OD): δ 8.07 (s, 1H), 7.76 (s, 1H),7.71 (d, J=7.6 Hz, 1H), 7.68 (s, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.31-7.28(m, 1H), 7.21-7.18 (m, 1H), 7.09-7.05 (m, 2H), 4.24 (t, J=7.2 Hz, 2H),2.02-1.97 (m, 2H), 1.86-1.82 (m, 1H), 1.01-0.97 (m, 5H), 0.85-0.82 (m,2H); MS (ESI): m/z 452.3 (M+H⁺); HPLC: 86.9%; (column: Acquity BEH C-18(50×2.1 mm, 1.7μ); RT 3.00 min; ACN: 0.025% TFA (aq); 0.5 mL/min.

Example 4 Synthesis of3-((2,6-dichloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoicacid (Compound 1-7)

Step 1: Synthesis of 6-chloro-7-fluoro-1H-indole (2)

To a stirred solution of 1-chloro-2-fluoro-3-nitrobenzene 1 (10.0 g,56.98 mmol) in THF (100 mL) under inert atmosphere was added vinylmagnesium bromide (1M in THF solution; 170 mL, 170.94 mmol) at RT,cooled to −40° C. and stirred for 30 min. The reaction was monitored byTLC; after completion of the reaction, the reaction mixture was quenchedwith saturated NH₄Cl solution (50 mL), extracted with EtOAc (2×50 mL).The combined organic extracts were washed with NH₄Cl solution (40 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure toobtain the crude. This was purified by silica gel column chromatographyusing 2% EtOAc/Hexanes to afford compound 2 (1.1 g, 11.4%) as a brownoil. ¹H NMR (500 MHz, CDCl₃): δ 8.36 (br s, 1H), 7.31 (d, J=8.0 Hz, 1H),7.25-7.22 (m, 1H), 7.08-7.05 (m, 1H), 6.56-6.54 (m, 1H).

Step 2: Synthesis of6-chloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indole (3)

To a stirred solution of compound 2 (1.1 g, 6.48 mmol) in toluene (15mL) under inert atmosphere were added N,N′-dimethyl ethylene diamine(229 mg, 2.60 mmol), potassium phosphate (3.44 g, 16.27 mmol),4-bromo-1-propyl-1H-pyrazole (Intermediate B; 1.21 g, 6.50 mmol), CuI(124 mg, 0.65 mmol) at RT, degassed under argon for 15 min; heated to140° C. and stirred for 20 h in sealed tube. The reaction was monitoredby TLC; after completion of the reaction, the reaction mixture wasdiluted with EtOAc (30 mL), filtered and the filtrate was concentratedunder reduced pressure to obtain the crude. This was purified by silicagel column chromatography using 8-10% EtOAc/Hexanes to afford compound 3(1.3 g, 72%) as brown liquid. ¹H NMR (500 MHz, CDCl₃): δ 7.64 (s, 1H),7.60 (s, 1H), 7.31 (d, J=7.5 Hz, 1H), 7.12-7.07 (m, 2H), 6.60 (s, 1H),4.13 (t, J=7.0 Hz, 2H), 1.99-1.91 (m, 2H), 0.97 (t, J=8.0 Hz, 3H); LC-MS(ESI): 93.5%; m/z 278.2 (M+H⁺); (column: X Select CSH C-18, 50×3.0 mm,3.5 μm); RT 4.08 min; 5 mM NH₄OAc: ACN; 0.8 mL/min).

Step 3: Synthesis of ethyl3-((6-chloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoate (4)

To a stirred solution of ethyl 3-mercaptobenzoate (66 mg, 0.36 mmol) inCH₂Cl₂ (5 mL) under inert atmosphere was added NCS (48.2 mg, 0.36 mmol)at RT and stirred for 50 min. To this, compound 3 (100 mg, 0.36 mmol)was added at RT and stirred for 16 h. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture was diluted withwater (25 mL) and extracted with CH₂Cl₂ (2×20 mL). The combined organicextracts were washed with brine (20 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to obtain the crude. This waspurified by silica gel column chromatography using 9% EtOAc/Hexanes toafford compound 4 (100 mg, 61%) as a colorless syrup. ¹H NMR (500 MHz,CDCl₃): δ 7.88 (s, 1H), 7.77-7.76 (m, 1H), 7.69 (s, 1H), 7.67 (s, 1H),7.43 (s, 1H), 7.27-7.24 (m, 3H), 7.15-7.12 (m, 1H), 4.33 (q, J=7.5 Hz,2H), 4.15 (t, J=7.0 Hz, 2H), 1.98-1.94 (m, 2H), 1.35 (t, J=7.5 Hz, 3H),0.98 (t, J=7.0 Hz, 3H); LC-MS: 94.6%; m/z 458.4 (M+H⁺); (column: XSelect CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.91 min; 5 mM NH₄OAc: ACN; 0.8mL/min).

Step 4: Synthesis of ethyl3-((2,6-dichloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoate(5)

To a stirred solution of compound 4 (150 mg, 0.32 mmol) in CH₂Cl₂ (3 mL)under inert atmosphere was added NCS (87 mg, 0.65 mmol) at RT. After 16h stirring, NCS (87 mg, 0.65 mmol) was added again at RT and stirred foradditional 24 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was diluted with water (15 mL) andextracted with CH₂Cl₂ (2×20 mL). The combined organic extracts werewashed with water (15 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to obtain the crude. This was purified by silicagel column chromatography using 7% EtOAc/n-Hexane to afford compound 5(100 mg, 62%) as a brown solid. ¹H NMR (500 MHz, CDCl₃): δ 7.89 (s, 1H),7.80-7.79 (m, 1H), 7.67 (s, 1H), 7.65 (s, 1H), 7.28-7.26 (m, 3H),7.17-7.14 (m, 1H), 4.33 (q, J=7.5 Hz, 2H), 4.18 (t, J=7.5 Hz, 2H),2.00-1.95 (m, 2H), 1.36 (t, J=7.5 Hz, 3H), 0.98 (t, J=7.5 Hz, 3H); LC-MS(ESI): 97.6%; m/z 492.4 (M+H⁺); (column: X Select CSH C-18, 50×3.0 mm,3.5 μm); RT 5.07 min; 5 mM NH₄OAc: ACN; 0.8 mL/min).

Step 5: Synthesis of3-((2,6-dichloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoicacid

To a stirred solution of compound 5 (100 mg, 0.20 mmol) in THF:EtOH:H₂O(3:1:1, 5 mL) under inert atmosphere was added LiOH.H₂O (25.6 mg, 0.61mmol) at RT and stirred for 5 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed underreduced pressure. The residue was diluted with water (10 mL), washedwith Et₂O (2×10 mL). The aqueous layer was acidified with 1N HCl andextracted with CH₂Cl₂ (2×20 mL). The combined organic extracts werewashed with water (15 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to obtain the crude. The crude was trituratedwith n-pentane (2×5 mL) to afford the title compound 1-7 (60 mg, 64%) asan off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 12.90 (br s, 1H), 8.31(s, 1H), 7.82 (s, 1H), 7.72-7.70 (m, 2H), 7.37-7.28 (m, 4H), 4.16 (t,J=6.8 Hz, 2H), 1.87-1.82 (m, 2H), 0.85 (t, J=7.6 Hz, 3H); MS (ESI): m/z464.2 (M+H⁺); HPLC: 99.1%; (column: Acquity BEH C-18 (50×2.1 mm, 1.7μ);RT 2.94 min; ACN: 0.025% TFA (aq); 0.5 mL/min.

Example 5 Synthesis of3-((2-bromo-6-chloro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoic acid (Compound 1-2)

To a stirred solution of ethyl3-((2-bromo-6-chloro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoate1 (Example 2, Step 3; 70 mg, 0.13 mmol) in THF:H₂O (1:1, 10 mL) underinert atmosphere was added LiOH.H₂O (17 mg, 0.40 mmol) at 0° C.; warmedto RT and stirred for 12 h. The reaction was monitored by TLC; aftercompletion of the reaction, the volatiles were removed under reducedpressure. The residue was diluted with water (15 mL), acidified withcitric acid to pH ˜2.0. The obtained solid was filtered and dried underreduced pressure to afford the title compound 1-2 (50 mg, 76%) as anoff-white solid. ¹H NMR (400 MHz, CD₃OD): δ 8.10 (s, 1H), 7.77-7.75 (m,3H), 7.49 (d, J=8.4 Hz, 1H), 7.32-7.30 (m, 2H), 7.20-7.16 (m, 2H), 4.24(t, J=7.2 Hz, 2H), 2.02-1.93 (m, 2H), 0.98 (t, J=7.2 Hz, 3H); LC-MS(ESI): 90.8%; m/z 488.8 (M−H⁺); (column: X Select CSH C-18, 50×3.0 mm,3.5 μm); RT 3.35 min; 5 mM NH₄OAc: ACN; 0.8 mL/min); HPLC: 96.4%;(column: Acquity BEH C-18 (50×2.1 mm, 1.7μ); RT 2.96 min; ACN: 0.025%TFA (aq); 0.5 mL/min.

Example 6 Synthesis of3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoicacid (Compound 1-10)

Step 1: Synthesis of ethyl3-((2-bromo-6-chloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoate(2)

To a stirred solution of ethyl3-((6-chloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoate1 (Example 4, Step 3; 500 mg, 1.09 mmol) in CCl₄ (10 mL) under inertatmosphere was added NBS (391 mg, 2.18 mmol) at RT and stirred for 16 h.The reaction was monitored by TLC; after completion of the reaction, thereaction mixture was diluted with water (30 mL) and extracted withCH₂Cl₂×30 mL). The combined organic extracts were washed with water (30mL), dried over Na₂SO₄, filtered and concentrated under reduced pressureto obtain the crude. This was purified by silica gel columnchromatography using 10% EtOAc/Hexanes to afford compound 2 (360 mg,62%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃): δ 7.89 (br s, 1H),7.80-7.78 (m, 1H), 7.67 (s, 1H), 7.65 (s, 1H), 7.29-7.27 (m, 2H),7.24-7.23 (m, 1H), 7.16-7.13 (m, 1H), 4.34 (q, J=7.2 Hz, 2H), 4.19 (t,J=6.8 Hz, 2H), 2.01-1.95 (m, 2H), 1.36 (t, J=6.8 Hz, 3H), 0.98 (t, J=7.2Hz, 3H); LC-MS (ESI): 97.6%; m/z 536.8 (M+H⁺); (column: X Select CSHC-18, 50×3.0 mm, 3.5 μm); RT 5.03 min; 5 mM NH₄OAc: ACN; 0.8 mL/min).

Step 2: Synthesis of ethyl3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoate(3)

To a stirred solution of compound 2 (360 mg, 0.67 mmol) in DME (5 mL)under inert atmosphere were added KOAc (197 mg, 2.01 mmol), Pd(dppf)Cl₂(98 mg, 0.13 mmol), cyclopropylboronic acid (57.8 mg, 0.67 mmol) at RTand degassed under Ar for 20 min; heated to 80° C. and stirred for 16 h.The reaction was monitored by TLC; after completion of the reaction, thereaction mixture was diluted with EtOAc (40 mL), filtered throughcelite. The filtrate was washed with water (25 mL), brine (25 mL), driedover Na₂SO₄ and concentrated under reduced pressure to obtain the crude.This was purified by silica gel column chromatography and thenpreparative HPLC to afford pure compound 3 (50 mg, 15%) as a whitesolid. ¹H NMR (500 MHz, CDCl₃): δ 7.79 (s, 1H), 7.74 (d, J=7.5 Hz, 1H),7.67 (s, 1H), 7.63 (s, 1H), 7.25-7.18 (m, 2H), 7.12 (d, J=8.0 Hz, 1H),7.06-7.05 (m, 1H), 4.33 (q, J=7.5 Hz, 2H), 4.18 (t, J=7.5 Hz, 2H),2.00-1.95 (m, 2H), 1.70-1.69 (m, 1H), 1.36 (t, J=7.5 Hz, 3H), 1.07-1.05(m, 2H), 0.99-0.97 (t, J=7.5 Hz, 3H), 0.87-0.84 (m, 2H); LC-MS (ESI):99.7%; m/z 498.5 (M+H⁺); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm);RT 5.11 min; 5 mM NH₄OAc: ACN; 0.8 mL/min).

Step 3: Synthesis of3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoicacid

To a stirred solution of compound 3 (50 mg, 0.10 mmol) in THF:EtOH:H₂O(3:1:1, 5 mL) under inert atmosphere was added LiOH.H₂O (12.6 mg, 0.30mmol) at RT and stirred for 8 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed underreduced pressure. The residue was diluted with water (20 mL), acidifiedwith 1N HCl to pH-2 and extracted with CH₂Cl₂ (2×20 mL). The combinedorganic extracts were dried over Na₂SO₄, filtered and concentrated underreduced pressure to obtain the crude. The crude was triturated withn-pentane (2×5 mL) and dried under reduced pressure to afford the titlecompound 1-10 (25 mg, 53%) as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆): δ 12.90 (br s, 1H), 8.26 (s, 1H), 7.79 (s, 1H), 7.66 (d, J=7.6Hz, 1H), 7.61 (s, 1H), 7.34 (t, J=7.6 Hz, 1H), 7.19-7.16 (m, 3H), 4.15(t, J=6.8 Hz, 2H), 1.87-1.78 (m, 3H), 0.95-0.92 (m, 2H), 0.87-0.80 (m,5H); MS (ESI): m/z 470.7 (M+H⁺); HPLC: 97.8%; (column: Acquity BEH C-18(50×2.1 mm, 1.7μ); RT 3.00 min; ACN: 0.025% TFA (aq); 0.5 mL/min.

Example 7 Synthesis of3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoicacid (Compound 1-16)

Step 1: Synthesis of ethyl3-((6-chloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoate(2)

To a stirred solution of ethyl 2-fluoro-3-mercaptobenzoate (IntermediateA; 108 mg, 0.54 mmol) in CH₂Cl₂ (3 mL) under inert atmosphere was addedNCS (72 mg, 0.54 mmol) at RT and stirred for 1 h. To this, compound 1(Example 4, Step 2; 150 mg, 0.54 mmol) was added and stirred for 16 h.The reaction was monitored by TLC; after completion of the reaction, thereaction mixture was diluted with water (25 mL) and extracted withCH₂Cl₂ (2×25 mL). The combined organic extracts were washed with brine(20 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to obtain the crude. This was purified by silica gel columnchromatography using 10% EtOAc/Hexanes to afford compound 2 (130 mg,50%) as an off-white solid. ¹H NMR (500 MHz, CDCl₃): δ 7.69 (s, 1H),7.67-7.64 (m, 2H), 7.44 (s, 1H), 7.29-7.27 (m, 1H), 7.17-7.14 (m, 1H),7.01-6.94 (m, 2H), 4.40 (q, J=7.5 Hz, 2H), 4.15 (t, J=8.0 Hz, 2H),1.98-1.94 (m, 2H), 1.40 (t, J=7.5 Hz, 3H), 0.98 (t, J=8.0 Hz, 3H); LC-MS(ESI): 97.6%; m/z 476.7 (M+H⁺); (column: X Select CSH C-18, 50×3.0 mm,3.5 μm); RT 4.84 min; 5 mM NH₄OAc: ACN; 0.8 mL/min).

Step 2: Synthesis of ethyl3-((2-bromo-6-chloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoate(3)

To a stirred solution of compound 2 (200 mg, 0.42 mmol) in CCl₄ (3 mL)under inert atmosphere was added NBS (150 mg, 0.84 mmol) at RT andstirred for 16 h. The reaction was monitored by TLC and LC-MS; aftercompletion of the reaction, the reaction mixture was diluted with water(20 mL) and extracted with CH₂Cl₂ (2×20 mL). The combined organicextracts were washed with brine (15 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to obtain the crude. This waspurified by silica gel column chromatography using 10-15% EtOAc/Hexanesto afford compound 3 (100 mg, 43%) as an off-white solid. ¹H NMR (400MHz, CDCl₃): δ 7.71-7.67 (m, 1H), 7.66 (s, 1H), 7.64 (s, 1H), 7.31 (d,J=8.8 Hz, 1H), 7.18-7.15 (m, 1H), 7.00-6.96 (m, 2H), 4.40 (q, J=7.2 Hz,2H), 4.18 (t, J=7.2 Hz, 2H), 2.02-1.93 (m, 2H), 1.40 (t, J=7.2 Hz, 3H),0.97 (t, J=7.2 Hz, 3H); LC-MS (ESI): 98.1%; m/z 556.2 (M⁺+2); (column: XSelect CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.94 min; 5 mM NH₄OAc: ACN; 0.8mL/min).

Step 3: Synthesis of ethyl3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoate(4)

To a stirred solution of compound 3 (260 mg, 0.47 mmol) in DME (5 mL)under inert atmosphere were added cyclopropylboronic acid (40.4 mg, 0.47mmol), Pd(dppf)₂Cl₂ (69 mg, 0.09 mmol), KOAc (138 mg, 1.41 mmol) at RT;heated to 90° C. and stirred for 16 h. The reaction was monitored byTLC; after completion of the reaction, the reaction mixture was dilutedwith water (20 mL) and extracted with EtOAc (2×25 mL). The combinedorganic extracts were washed with brine (20 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to obtain the crude.This was purified by silica gel column chromatography using 7-9%EtOAc/Hexanes to afford 70 mg of compound 4 which was further purifiedby preparative HPLC to afford pure compound 4 (20 mg, 9%) as a yellowsyrup. ¹H NMR (400 MHz, CDCl₃): δ 7.67 (s, 1H), 7.64-7.60 (m, 2H), 7.18(d, J=8.8 Hz, 1H), 7.10-7.06 (m, 1H), 6.95-6.91 (m, 1H), 6.79-6.75 (m,1H), 4.41 (q, J=7.2 Hz, 2H), 4.18 (t, J=7.2 Hz, 2H), 2.00-1.93 (m, 2H),1.74-1.67 (m, 1H), 1.41 (t, J=7.2 Hz, 3H), 1.08-1.06 (m, 2H), 0.99 (t,J=7.2 Hz, 3H), 0.87-0.84 (m, 2H); LC-MS (ESI): 99.9%; m/z 516.5 (M+H⁺);(column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 5.00 min; 5 mMNH₄OAc: ACN; 0.8 mL/min).

Step 4: Synthesis of3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoicacid

To a stirred solution of compound 4 (30 mg, 0.058 mmol) in THF:EtOH:H₂O(3:1:1, 2.5 mL) under inert atmosphere was added LiOH.H₂O (7.3 mg, 0.17mmol) at RT and stirred for 8 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed underreduced pressure. The residue was diluted with water (10 mL), washedwith Et₂O (2×10 mL). The aqueous layer was acidified with 1N HClsolution and extracted with CH₂Cl₂ (2×15 mL). The combined organicextracts were washed with brine (15 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to obtain the crude. This wastriturated with n-pentane (5 mL) to afford the title compound 1-16 (25mg, 89%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.25 (s,1H), 7.80 (s, 1H), 7.18-7.14 (m, 3H), 6.81 (t, J=7.6 Hz, 1H), 6.42 (t,J=7.6 Hz, 1H), 4.15 (t, J=6.8 Hz, 2H), 1.87-1.76 (m, 3H), 0.95-0.93 (m,2H), 0.86-0.80 (m, 5H); MS (ESI): m/z 488.4 (M+H⁺) HPLC: 99.7%; (column:Acquity BEH C-18 (50×2.1 mm, 1.7μ); RT 2.88 min; ACN: 0.025% TFA (aq);0.5 mL/min.

Example 8 Synthesis of3-((2,6-dichloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoicacid (Compound 1-13)

Step 1: Synthesis of ethyl3-((2,6-dichloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoate(2)

To a stirred solution of ethyl3-((6-chloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoate1 (Example 7, Step 1; 100 mg, 0.21 mmol) in CH₂Cl₂ (3 mL) was added NCS(33.7 mg, 0.25 mmol) at RT under inert atmosphere. After 8 h stirring,additional NCS (33.7 mg, 0.25 mmol) was added at RT and stirred againfor 24 h. The reaction was monitored by TLC; after completion of thereaction, the reaction mixture was diluted with water (20 mL) andextracted with CH₂Cl₂ (2×20 mL). The combined organic extracts werewashed with brine (15 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to obtain the crude. This was purified by silicagel column chromatography using 9-11% EtOAc/Hexanes to afford compound 2(50 mg, 47%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃): δ 7.71-7.67(m, 1H), 7.66 (s, 1H), 7.64 (s, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.18 (dd,J=8.4, 6.0 Hz, 1H), 7.04-6.97 (m, 2H), 4.40 (q, J=7.2 Hz, 2H), 4.18 (t,J=7.2 Hz, 2H), 2.04-1.93 (m, 2H), 1.40 (t, J=7.2 Hz, 3H), 0.97 (t, J=7.2Hz, 3H); LC-MS (ESI): 98.8%; m/z 510.4 (M+H⁺); (column: X Select CSHC-18, 50×3.0 mm, 3.5 μm); RT 4.94 min; 5 mM NH₄OAc: ACN; 0.8 mL/min).

Step 2: Synthesis of3-((2,6-dichloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoicacid

To a stirred solution of compound 2 (50 mg, 0.09 mmol) in THF:EtOH:H₂O(3:1:1, 5 mL) under inert atmosphere was added LiOH.H₂O (12.3 mg, 0.29mmol) at RT and stirred for 5 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed underreduced pressure. The residue was diluted with water (10 mL), acidifiedwith 1N HCl and extracted with CH₂Cl₂ (2×10 mL). The combined organicextracts were washed with brine (10 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to obtain the crude. This wastriturated with n-pentane (2×5 mL) to afford the title compound 1-13 (15mg, 34%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ13.24 (br s,1H), 8.29 (s, 1H), 7.83 (s, 1H), 7.64-7.60 (m, 1H), 7.36-7.34 (m, 2H),7.15-7.05 (m, 2H), 4.16 (t, J=7.2 Hz, 2H), 1.89-1.80 (m, 2H), 0.85 (t,J=7.2 Hz, 3H); MS (ESI): 480.1 (M−H⁺); HPLC: 97.0%; (column: Acquity BEHC-18 (50×2.1 mm, 1.7μ); RT 2.86 min; ACN: 0.025% TFA (aq); 0.5 mL/min.

Example 9 Synthesis of3-((6-Chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoicacid (Compound 1-34) Route 1

Step 1: Synthesis of1-(2-amino-4-chloro-3-fluorophenyl)-2-chloroethan-1-one (2)

To a stirred solution of AlCl₃ (10.0 g, 75.01 mmol) and BCl₃ (1M inn-hexane) (74 mL, 75.01 mmol) in CH₂Cl₂ (80 mL) was added3-chloro-2-fluoroaniline 1 (9.0 g, 6.18 mmol) followed by a solution ofchloroacetonitrile (11.6 g, 153.64 mmol) in CH₂Cl₂ (20 mL) at 0° C.under inert atmosphere. The reaction mixture was allowed to stir at RTfor 30 minutes; heated to reflux temperature and maintained foradditional 14 h. The reaction mixture was then cooled to 0° C., addedaqueous 3N HCl solution (100 mL) and raised the temperature to refluxand stirred for 3 h. After completion of the reaction by TLC, thereaction mixture was cooled RT, diluted with water (50 mL) and extractedwith CH₂Cl₂ (2×150 mL). The combined organic extracts were dried overNa₂SO₄, filtered and concentrated under reduced pressure to obtain thecrude. The crude was purified by triturating with n-pentane to affordcompound 2 (4.5 g, 33%) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆): δ 7.61 (d, J=9.0 Hz, 1H), 7.35 (br s, 2H), 6.72 (d, J=9.0 Hz,1H), 5.06 (s, 2H).

Step 2: Synthesis of 6-chloro-2-cyclopropyl-7-fluoro-1H-indole (3)

To a stirred solution of compound 2 (4.5 g, 20.3 mmol) in toluene (50mL) was added cyclopropyl magnesium bromide (0.5 M in THF; 102.0 mL,50.9 mmol) at 0° C. under inert atmosphere. The reaction mixture wasstirred at 0° C. for 15 min and then warmed to RT and stirring wascontinued for additional 1 h. After completion of the reaction by TLC,the reaction mixture was quenched with saturated ammonium chloridesolution (10 mL) and extracted with EtOAc (3×75 mL). The combinedorganic extracts were dried over Na₂SO₄, filtered and concentrated underreduced pressure to obtain the crude. The crude was purified (silica gelchromatography; 1% EtOAc/Hexanes) to afford compound 3 (2.7 g, 63%) asan off-white solid. ¹H NMR (500 MHz, DMSO-d₆): δ 11.55 (s, 1H), 7.18 (d,J=8.5 Hz, 1H), 6.97 (dd, J=8.5, 6.5 Hz, 1H), 6.16 (s, 1H), 2.03-1.99 (m,1H), 0.99-0.96 (m, 2H), 0.83-0.80 (m, 2H); LC-MS (ESI): 91.6%; m/z 208.1(M −H⁺); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.32 min; 5mM NH₄OAc: ACN; 0.8 mL/min).

Step 3: Synthesis of 4-bromo-1-ethyl-1H-pyrazole (4)

To a stirred solution of NaH (34.0 g, 0.85 mol; 60% in mineral oil) inTHF (400 mL) was added a solution of 4-bromo-1H-pyrazole (50 g, 0.34mol) in THF (100 mL) at 0° C. under inert atmosphere. The reactionmixture was warmed to RT and maintained at same temperature for 1 h. Thereaction mixture was cooled again to 0° C. and added EtI (63.67 g, 0.408mol) slowly for 5 min. The resultant solution was allowed to warm to RTand then stirred for 16 h. After completion of the reaction (monitoredby TLC), the reaction mixture was quenched with ice-cold water (100 mL)and extracted with EtOAc (3×250 mL). The combined organic extracts weredried over Na₂SO₄, filtered and concentrated under reduced pressure toobtain the crude. The crude was purified (silica gel chromatography;4-6% EtOAc/Hexanes) to afford compound 4 (43 g, 72%) as a pale yellowliquid. ¹H NMR (500 MHz, CDCl₃): δ 7.45 (s, 1H), 7.41 (s, 1H), 4.15 (q,J=7.5 Hz, 2H), 1.47 (t, J=7.5 Hz, 3H); MS (ESI): m/z 175.0 (M+H⁺).

Step 4: Synthesis of6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indole(5)

To a solution of compound 3 (4.3 g, 20.5 mmol) in toluene (50 mL) wereadded 4-bromo-1-ethyl-1H-pyrazole 4 (4.0 g, 22.8 mmol), potassiumphosphate (11.0 g, 51.2 mmol), N,N′-dimethylethylenediamine (722 mg, 8.2mmol) and Cu(I)I (390 mg, 2.0 mmol) at RT under inert atmosphere. Thereaction solution was purged with argon for 15 min and then sealed thetube. The reaction mixture was heated to 140° C. and stirred for 16 h.After completion of the reaction by TLC, the reaction mixture was cooedto RT, diluted with EtOAc (50 mL) and filtered. The filtrate was washedwith water (40 mL), brine (40 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to obtain the crude. The crude waspurified (silica gel chromatography; 9% EtOAc/Hexanes) to affordcompound 5 (3.9 g, 63%) as a pale brown solid. ¹H NMR (400 MHz, CDCl₃):δ 7.64 (s, 1H), 7.60 (s, 1H), 7.16 (d, J=8.4 Hz, 1H), 7.01 (dd, J=8.4,6.4 Hz, 1H), 6.12 (s, 1H), 4.25 (q, J=7.2 Hz, 2H), 1.69-1.62 (m, 1H),1.56 (t, J=7.2 Hz, 3H), 0.92-0.87 (m, 2H), 0.76-0.72 (m, 2H); LC-MS(ESI): 98.6%; m/z 304.3 (M+H⁺); (column: X Select C-18, 50×3.0 mm, 3.5μm); RT 4.23 min; 5 mM NH₄OAc: ACN; 0.8 mL/min).

Step 5: Synthesis of ethyl 3-bromo-2-fluorobenzoate (A2)

To a stirred solution of 3-bromo-2-fluorobenzoic acid A1 (25.0 g, 114.15mmol) in ethanol (400 mL) was added conc. H₂SO₄ (3 mL) at RT and stirredat reflux temperature for 24 h. The reaction was monitored by LC-MS;after completion of the reaction, the reaction mixture was concentratedto obtain the residue. The residue was diluted with EtOAc (500 mL),washed with water (300 mL), brine (300 mL), dried over Na₂SO₄, filteredand concentrated under reduced pressure to afford compound A2 (26.0 g,92%) as a light yellow liquid. ¹H NMR (400 MHz, CDCl₃): δ 7.88-7.84 (m,1H), 7.72-7.69 (m, 1H), 7.08-7.04 (m, 1H), 4.39 (q, J=7.2 Hz, 2H), 1.39(t, J=7.2 Hz, 3H).

Step 6: Synthesis of ethyl 2-fluoro-3-((4-methoxybenzyl)thio)benzoate(A3)

1,4-dioxane (250 mL) was degassed by purging with N₂ gas for 30 min andto this, were added a solution of compound A2 (13.2 g, 53.4 mmol) in1,4-dioxane (50 mL; degassed), (4-methoxyphenyl)methanethiol (PMBSH)(8.2 g, 53.4 mmol), xantphos (1.54 g, 2.66 mmol), diisopropyl ethylamine (19.6 mL, 106.8 mmol) and Pd₂(dba)₃ (1.22 g, 1.33 mmol) at RT. Thereaction mixture was heated to 90° C. and stirred for 2 h. The reactionwas monitored by TLC; after completion of the reaction, the reactionmixture was diluted with hexane (450 mL) and stirred at RT for 15 min.The resultant solution was filtered through celite and washed withhexane (100 mL). The filtrate was washed water (250 mL) dried overNa₂SO₄, filtered and concentrated under reduced pressure to obtain thecrude. The crude was purified through silica gel column chromatographyusing 3-4% EtOAc/Hexanes to afford compound A3 (15 g, 88%) as paleyellow solid. ¹H NMR (500 MHz, CDCl₃): δ 7.78-7.74 (m, 1H), 7.43-7.39(m, 1H), 7.19 (d, J=8.0 Hz, 2H), 7.07-7.04 (m, 1H), 6.80 (d, J=8.0 Hz,2H), 4.41 (q, J=7.2 Hz, 2H), 4.08 (s, 2H), 3.78 (s, 3H), 1.41 (t, J=7.2Hz, 3H). LC-MS (ESI): 89.7%; m/z 318.9 (M−H⁺); (column: X Select CSHC-18, 50×3.0 mm, 3.5 μm); RT 4.22 min; 5 mM NH₄OAc: ACN; 0.8 mL/min).

Step 7: Synthesis of ethyl 2-fluoro-3-mercaptobenzoate (6)

A stirred solution of compound A3 (30.0 g, 93.75 mmol) in TFA (54.5 mL)was heated to 80° C. and stirred for 12 h under inert atmosphere. Thereaction was monitored by TLC; after completion of the reaction, thevolatiles were removed under reduced pressure. The residue was dissolvedin ice-cold water (100 mL), basified with solid sodium bicarbonate andextracted with EtOAc (2×200 mL). The combined organic extracts weredried over Na₂SO₄, filtered and concentrated under reduced pressure toobtain the crude. The crude was purified through silica gel columnchromatography using 3% EtOAc/Hexanes to afford compound 6 (11.7 g, 62%)as a pale brown syrup. ¹H NMR (500 MHz, CDCl₃): δ 7.70-7.66 (m, 1H),7.48-7.44 (m, 1H), 7.08-7.04 (m, 1H), 4.20 (q, J=7.5 Hz, 2H), 3.67 (s,1H), 1.40 (t, J=7.5 Hz, 3H); LC-MS (ESI): 91.8%; m/z 199.0 (M−H⁺);(column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 2.60 min; 5 mMNH₄OAc: ACN; 0.8 mL/min).

Step 8: Synthesis of ethyl3-((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoate(7)

To a stirred solution of ethyl 2-fluoro-3-mercaptobenzoate 6 (2.8 g,14.0 mmol) in CH₂Cl₂ (30 mL) under inert atmosphere was added NCS (1.9g, 14.0 mmol) at RT and allowed to stir for 2 h. To this, compound 5(3.9 g, 12.8 mmol) in CH₂Cl₂ (10 mL) was added at RT and stirred for 16h. After completion of the reaction by TLC, the reaction mixture wasdiluted with water (100 mL) and extracted with CH₂Cl₂ (2×80 mL). Thecombined organic extracts were washed with water (2×200 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to obtain thecrude. The crude was purified by triturating with n-pentane (2×50 mL) toafford 7 (5.2 g, 81%) as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃): δ7.66-7.7.60 (m, 3H), 7.18 (d, J=8.4 Hz, 1H), 7.08 (dd, J=8.4, 6.5 Hz,1H), 6.93 (t, J=8.4 Hz, 1H), 6.79-6.75 (m, 1H), 4.40 (q, J=7.2 Hz, 2H),4.26 (q, J=7.6 Hz, 2H), 1.74-1.68 (m, 1H), 1.56 (t, J=7.2 Hz, 3H), 1.41(t, J=7.6 Hz, 3H), 1.08-1.04 (m, 2H), 0.89-0.84 (m, 2H); MS (ESI): m/z502.5 (M+H⁺); HPLC: 97.5%; (column: Acquity BEH C-18 (50×2.1 mm, 1.7μ);RT 3.44 min; ACN: 0.025% TFA (aq); 0.5 mL/min.

Step 9: Synthesis of3-((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoicacid sodium salt (Compound 1-34 sodium salt)

1.0 M NaOH (10.25 mL, 10.2 mmol) was added to a solution of compound 7(5.14 g, 10.2 mmol) in THF/MeOH (3:1)(56 mL). The mixture was heated at65° C. for 1.5 h. Additional 1.0 M NaOH (0.23 mL, 0.2 mmol) was added tothe reaction and heated at 65° C. for 0.5 h. The mixture wasconcentrated under reduced pressure to afford the crude acid sodium salt(5.12 g, 100%) as a pale pink solid. The crude solid (600 mg) inTHF/EtOH (4:1) (6 mL) and a few drops of water. The mixture filtered andconcentrated under reduced pressure and precipitants formed. The solidsfiltered off and washed with THF/EtOH (9:1) to afford3-((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoicacid sodium salt (Compound 1-34 sodium salt; 449 mg) as an off whitesolid. ¹H NMR (300 MHz, DMSO-d₆): δ 8.26 (s, 1H), 7.79 (m, 1H),7.18-7.13 (m, 3H), 6.81 (t, 1H), 6.43-6.38 (m, 1H), 4.21 (q, 2H),1.84-1.72 (m, 1H), 1.42 (t, 3H), 0.96-0.93 (m, 2H), 0.84-0.80 (m, 2H);LC-MS: 474 (M⁺).

Step 9:3-((6-Chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoicacid (Compound 1-34)

To Compound 1-34 sodium salt (50 mg, 0.10 mmol) suspended in CH₂Cl₂ (1mL) and water (1 mL) was added saturated citric acid until pH 3. Thesuspension stirred until clear solution. The organic layer wasseparated, washed with brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to obtain the crude material toafford compound B as a white solid (33 mg, 70%) ¹H NMR (300 MHz,DMSO-d₆): δ 13.39 (s, 1H), 8.24 (s, 1H), 7.79 (s, 1H), 7.57 (t, 1H),7.22-7.06 (m, 3H), 6.80 (t, 1H), 4.21 (q, 2H), 1.84-1.72 (m, 1H), 1.42(t, 3H), 0.96-0.88 (m, 2H), 0.86-0.80 (m, 2H); LC-MS: 474 (M⁺).

Alternative Route to Intermediate 7

Step 1: Synthesis of6-chloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indole (9)

To a stirred solution of 6-chloro-7-fluoro-1H-indole 8 (400 mg, 2.36mmol) in toluene (10 mL) were added 4-bromo-1-ethyl-1H-pyrazole 4 (Step3 above; 414 mg, 2.36 mmol), potassium phosphate (1.25 g, 5.91 mmol),N,N′-dimethylethylenediamine (84 mg, 0.95 mmol) and Cu(I)I (45 mg, 0.24mmol) at RT under inert atmosphere. The resulted solution was purgedwith argon and sealed the tube. The reaction mixture was then heated to140° C. for 16 h. After completion of the reaction (monitored by TLC),the reaction mixture was cooled to RT, diluted with hexane (10 mL) andfiltered through a short pad of celite. The filtrate was washed withwater (2×10 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to obtain the crude. The crude was purified (silica gelchromatography; 8-10% EtOAc/Hexanes) to afford compound 9 (224 mg, 36%)as a light brown thick liquid. ¹H NMR (500 MHz, CDCl₃): δ 7.64 (s, 1H),7.61 (s, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.12-7.07 (m, 2H), 6.60-6.59 (m,1H), 4.22 (q, J=7.5 Hz, 2H), 1.55 (t, J=7.5 Hz, 3H); LC-MS (ESI): 94.7%;m/z 264.1 (M+H⁺); (column: X Select C-18, 50×3.0 mm, 3.5 μm); RT 3.87min; 5 mM NH₄OAc: ACN; 0.8 mL/min).

Step 2: Synthesis of ethyl3-((6-chloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoate(10)

To a stirred solution of ethyl 2-fluoro-3-mercaptobenzoate 6 (Step 7above; 212 mg, 1.06 mmol) in CH₂Cl₂ (4 mL) under inert atmosphere wasadded NCS (156 mg, 1.16 mmol) at 0° C. and allowed to stir at RT for 1h. The reaction mixture was cooled to 0° C. and compound 3 (280 mg, 1.06mmol) in CH₂Cl₂ (1 mL) was added slowly and stirred at RT for 16 h.After completion of the reaction by TLC, the reaction mixture wasdiluted with CH₂Cl₂ (15 mL) and washed with water (2×20 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to obtain thecrude. The crude was purified (silica gel chromatography; 8-10%EtOAc/Hexanes) to afford compound 10 (300 mg, 61%) as a pale brownsolid. ¹H NMR (500 MHz, CDCl₃): δ 7.69-7.64 (m, 3H), 7.44 (s, 1H), 7.27(t, J=8.0 Hz, 1H), 7.16 (dd, J=8.5, 6.0 Hz, 1H), 7.01-6.94 (m, 2H), 4.39(q, J=7.5 Hz, 2H), 4.24 (q, J=7.0 Hz, 2H), 1.57 (t, J=7.0 Hz, 3H), 1.40(t, J=7.5 Hz, 3H); LC-MS (ESI): 98.6%; m/z 462.3 (M+H⁺); (column: XSelect C-18, 50×3.0 mm, 3.5 μm); RT 4.70 min; 5 mM NH₄OAc: ACN; 0.8mL/min).

Step 3: Synthesis of ethyl3-((2-bromo-6-chloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoate(11)

To a stirred solution of compound 10 (200 mg, 0.43 mmol) in CCl₄ (10 mL)under inert atmosphere was added NBS (178 mg, 0.99 mmol) at RT andstirred for 16 h. After completion of the reaction by TLC, the reactionmixture was diluted with water (10 mL) and extracted with CH₂Cl₂ (2×20mL). The combined organic extracts were washed with brine (10 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to obtainthe crude. The crude was purified (silica gel chromatography; 5-7%EtOAc/Hexanes) to afford compound 11 (180 mg, 77%) as an off-whitesolid. ¹H NMR (500 MHz, CDCl₃): δ 7.70-7.67 (m, 1H), 7.65 (s, 2H), 7.30(d, J=8.0 Hz, 1H), 7.17 (dd, J=8.5, 6.0 Hz, 1H), 7.00-6.98 (m, 2H), 4.40(q, J=7.5 Hz, 2H), 4.27 (q, J=7.5 Hz, 2H), 1.58 (t, J=7.5 Hz, 3H), 1.40(t, J=7.5 Hz, 3H); LC-MS (ESI): 99.5%; m/z 542.4 (M+2); (column: XSelect CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.80 min; 5 mM NH₄OAc: ACN; 0.8mL/min).

Step 4: Synthesis of ethyl3-((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoate(7)

A solution of compound 11 (150 mg, 0.27 mmol) in toluene (10 mL) underinert atmosphere was purged with argon at RT for 10 min. To this,cyclopropylboronic acid (48 mg, 0.55 mmol), tricyclohexyl phosphine (16mg, 0.05 mmol), Pd(OAc)₂ (6 mg, 0.02 mmol) and potassium phosphate (202mg, 0.01 mmol) were added at RT under argon. The resultant solution waspurged again with argon at RT for 5 min. The reaction mixture was thenheated to reflux temperature and stirred for 3 h. The reaction wasmonitored by TLC & LC-MS; after completion of the reaction, the reactionwas cooled to RT, diluted with EtOAc (20 mL) and filtered. The filtratewas washed with water (2×10 mL) and brine (10 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to obtain the crude.This was purified (silica gel chromatography; 6% EtOAc/Hexanes) toafford 7 as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 7.66-7.7.60(m, 3H), 7.18 (d, J=8.4 Hz, 1H), 7.08 (dd, J=8.4, 6.5 Hz, 1H), 6.93 (t,J=8.4 Hz, 1H), 6.79-6.75 (m, 1H), 4.40 (q, J=7.2 Hz, 2H), 4.26 (q, J=7.6Hz, 2H), 1.74-1.68 (m, 1H), 1.56 (t, J=7.2 Hz, 3H), 1.41 (t, J=7.6 Hz,3H), 1.08-1.04 (m, 2H), 0.89-0.84 (m, 2H); LC-MS (ESI): 92.9%; m/z 502.5(M⁺); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.85 min; 5 mMNH₄OAc: ACN; 0.8 mL/min); HPLC: 93.1%; (column: Acquity BEH C-18 (50×2.1mm, 1.7μ); RT 3.44 min; ACN: 0.025% TFA (aq); 0.5 mL/min.

Example 10 Synthesis of6-((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)picolinicacid (Compound 1-92)

Step 1: Synthesis of1-(2-amino-4-chloro-3-fluorophenyl)-2-chloroethan-1-one (2)

To a stirred solution of AlCl₃ (10.0 g, 75.01 mmol) and BCl₃ (1M inn-hexane) (74 mL, 75.01 mmol) in CH₂Cl₂ (80 mL) was added3-chloro-2-fluoroaniline 1 (9.0 g, 6.18 mmol) followed by a solution ofchloroacetonitrile (11.6 g, 153.64 mmol) in CH₂Cl₂ (20 mL) at 0° C.under inert atmosphere. The reaction mixture was allowed to stir at RTfor 30 minutes; heated to reflux temperature and maintained foradditional 14 h. The reaction mixture was then cooled to 0° C., addedaqueous 3N HCl solution (100 mL) and raised the temperature to refluxand stirred for 3 h. After completion of the reaction (TLC), thereaction mixture was cooled RT, diluted with water (50 mL) and extractedwith CH₂Cl₂ (2×150 mL). The combined organic extracts were dried overNa₂SO₄, filtered and concentrated under reduced pressure to obtain thecrude. The crude was purified by triturating with n-pentane to affordcompound 2 (4.5 g, 33%) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆): δ 7.61 (d, J=9.0 Hz, 1H), 7.35 (br s, 2H), 6.72 (d, J=9.0 Hz,1H), 5.06 (s, 2H).

Step 2: Synthesis of 6-chloro-2-cyclopropyl-7-fluoro-1H-indole (3)

To a stirred solution of compound 2 (4.5 g, 20.3 mmol) in toluene (50mL) was added cyclopropyl magnesium bromide (0.5 M in THF; 102.0 mL,50.9 mmol) at 0° C. under inert atmosphere. The reaction mixture wasstirred at 0° C. for 15 min and then warmed to RT and stirring wascontinued for additional 1 h. After completion of the reaction (TLC),the reaction mixture was quenched with sat. NH₄Cl solution (10 mL) andextracted with EtOAc (3×75 mL). The combined organic extracts were driedover Na₂SO₄, filtered and concentrated under reduced pressure to obtainthe crude. The crude was purified (silica gel column chromatography; 1%EtOAc/Hexanes to afford compound 3 (2.7 g, 63%) as an off-white solid.¹H NMR (500 MHz, DMSO-d₆): δ 11.55 (s, 1H), 7.18 (d, J=8.5 Hz, 1H), 6.97(dd, J=8.5, 6.5 Hz, 1H), 6.16 (s, 1H), 2.03-1.99 (m, 1H), 0.99-0.96 (m,2H), 0.83-0.80 (m, 2H); LC-MS (ESI): 91.6%; m/z 208.1 (M−H⁺); (column: XSelect CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.32 min; 5 mM NH₄OAc: ACN; 0.8mL/min).

Step 3: Synthesis of6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indole(5)

To a solution of compound 3 (4.3 g, 20.5 mmol) in toluene (50 mL) wereadded 4-bromo-1-ethyl-1H-pyrazole 4 (Example 2, Step 3; 4.0 g, 22.8mmol), potassium phosphate (11.0 g, 51.2 mmol),N,N′-dimethylethylenediamine (722 mg, 8.2 mmol) and Cu(I)I (390 mg, 2.0mmol) at RT under inert atmosphere. The reaction solution was purgedwith argon for 15 min and then sealed the tube. The reaction mixture washeated to 140° C. and stirred for 16 h. After completion of the reaction(TLC), the reaction mixture was cooled to RT, diluted with EtOAc (50 mL)and filtered. The filtrate was washed with water (40 mL), brine (40 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure toobtain the crude. The crude was purified (silica gel columnchromatography; 9% EtOAc/Hexanes) to afford compound 5 (3.9 g, 63%) as apale brown solid. ¹H NMR (400 MHz, CDCl₃): δ 7.64 (s, 1H), 7.60 (s, 1H),7.16 (d, J=8.4 Hz, 1H), 7.01 (dd, J=8.4, 6.4 Hz, 1H), 6.12 (s, 1H), 4.25(q, J=7.2 Hz, 2H), 1.69-1.62 (m, 1H), 1.56 (t, J=7.2 Hz, 3H), 0.92-0.87(m, 2H), 0.76-0.72 (m, 2H); LC-MS (ESI): 98.6%; m/z 304.3 (M+H⁺);(column: X Select C-18, 50×3.0 mm, 3.5 μm); RT 4.23 min; 5 mM NH₄OAc:ACN; 0.8 mL/min).

Step 4: Synthesis of methyl 6-((4-methoxybenzyl) thio) picolinate (8)

To a stirred solution of methyl 6-bromopicolinate 7 (8 g, 37.2 mmol) in1, 4-dioxane (110 mL) under inert atmosphere were added(4-methoxyphenyl) methanethiol (5.7 g, 37.0 mmol), xantphos (1.1 g, 1.9mmol), diisopropyl ethyl amine (13.6 mL, 74.0 mmol), Pd₂(dba)₃ (847 mg,0.9 mmol) at RT, degassed under argon for 15 min; heated to reflux andstirred for 1 h. After completion of the reaction (TLC), the reactionmixture was diluted with water (500 mL) and extracted with EtOAc (3×500mL). The combined organic extracts were dried over Na₂SO₄, filtered andconcentrated under reduced pressure to obtain the crude. The crude waspurified (silica gel column chromatography; 10% EtOAc/hexanes) to affordcompound 8 (8 g, 75%) as yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 7.78(d, J=7.6 Hz, 1H), 7.57 (t, J=8.0 Hz, 1H), 7.42-7.40 (m, 2H), 7.29-7.25(m, 1H), 6.82 (d, J=8.4 Hz, 2H), 4.44 (s, 2H), 4.00 (s, 3H), 3.77 (s,3H); LC-MS: 95.7%; 290.3 (M⁺+1); (column: X Select C-18, 50×3.0 mm, 3.5μm); RT 4.10 min. 5 mM NH₄OAc: ACN; 0.8 mL/min).

Step 5: Synthesis of methyl 6-mercaptopicolinate (6)

A stirred solution of compound 8 (6 g, 20.7 mmol) in Trifluoro aceticacid (50 mL) under inert atmosphere was heated to reflux and stirred for16 h. After completion of the reaction (TLC), the volatiles were removedunder reduced pressure. The residue was diluted with EtOAc (500 mL),washed with aqueous NaHCO₃ solution (3×250 mL). The organic extract weredried over Na₂SO₄, filtered and concentrated under reduced pressure toobtain the compound 6 (3.5 g, crude) as pale brown solid. LC-MS: 61.1%;170 (M⁺+1); (column: X Select C-18, 50×3.0 mm, 3.5 μm); RT 1.41 min. 5mM NH₄OAc: ACN; 0.8 mL/min).

Step 6: Synthesis of methyl6-((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)picolinate(9)

To a stirred solution of methyl 6-mercaptopicolinate 6 (3.15 g, crude)in CH₂Cl₂ (50 mL) under inert atmosphere was added NCS (2.49 g, 18.63mmol) at RT and stirred for 1 h. To this, indole 5 (5.6 g, 18.47 mmol)in CH₂Cl₂ (50 mL) was added at RT and stirred for 16 h. After completionof the reaction (TLC), the reaction mixture was diluted CH₂Cl₂ (100 mL)washed with water (3×100 mL). The organic extract was dried over Na₂SO₄,filtered and concentrated under reduced pressure to obtain the crude.The crude was purified (silica gel column chromatography; 10%EtOAc/hexanes) to afford 9 (2.8 g, 32%) as a pale brown solid. ¹H NMR(500 MHz, DMSO-d₆): δ 7.79 (d, J=7.5 Hz, 1H), 7.66 (d, J=10.5 Hz, 2H),7.51 (t, J=7.5 Hz, 1H), 7.19 (d, J=8.5 Hz, 1H), 7.10-7.07 (m, 1H), 6.78(d, J=8.0 Hz, 1H), 4.28 (q, 2H), 4.00 (s, 3H), 1.75-1.69 (m, 1H), 1.58(t, J=7.0 Hz, 3H), 1.09-1.08 (m, 2H), 0.87-0.84 (m, 2H); LC-MS: 98.4%;m/z 471.4 (M+H⁺); (column; X-select CSH C-18, (50×3.0 mm, 3.5 μm); RT4.25 min. 5.0 mM NH₄OAc (Aq): ACN; 0.8 mL/min); HPLC: 98.1%; (column:Acquity BEH C-18 (50×2.1 mm, 1.7μ); RT 3.02 min. ACN: 0.025% TFA (aq);0.5 mL/min).

Step 7: Synthesis of6-((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)picolinicacid sodium salt (Compound 1-92 sodium salt)

To a stirred solution of compound 9 (2.81 g, 5.97 mmol) in THF:water(4:1) (40 mL) was added 1M aq. NaOH solution (6.03 mL, 6.03 mmol) andthe mixture was heated at 60° C. for 1 h. After completion of thereaction, the solvent was removed to afford Compound 1-92 (2.83 g, 100%)as a light brown solid. LC-MS: 457 (M⁺+1).

Example 11 Synthesis of3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoicacid sodium salt (Compound 1-119)

Step 1: Synthesis of ethyl3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-((2-(trimethylsilyl) ethoxy)methyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoate (3)

Following the procedure of Example 9, Steps 3 and 4 but usingIntermediate D in place of Intermediate B in Step 3, the title compound3 was obtained as a pale brown syrup. ¹H NMR (400 MHz, CDCl₃): δ 7.85(s, 1H), 7.73 (s, 1H), 7.64 (t, J=7.5 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H),7.12-7.09 (m, 1H), 6.95 (t, J=7.5 Hz, 1H), 6.79 (t, J=6.5 Hz, 1H), 5.54(s, 2H), 4.42 (q, 2H), 3.62 (t, J=7.5 Hz, 2H), 1.70-1.65 (m, 1H), 1.42(t, J=7.0 Hz, 3H), 1.06-1.05 (m, 2H), 0.96 (t, J=8.5 Hz, 2H), 0.89-0.87(m, 2H), 0.03 (s, 9H); LC-MS (ESI): m/z 604.6 (M+H⁺).

Step 2: Synthesis of ethyl3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoate(4)

To a stirred solution of compound 3 (140 mg, 0.23 mmol) in EtOH (17 mL)was added 3 N HCl (4 mL) at RT and heated to reflux for 3 h. Aftercompletion of the reaction (TLC), the pH of the mixture was neutralizedwith Et₃N (2 mL) and extracted with EtOAc (2×30 mL). The combinedorganic extracts were dried (Na₂SO₄), filtered and concentrated underreduced pressure to obtain the crude. The crude was titurated withn-pentane, dried under reduced pressure to afford 4 (90 mg, 90%) as apale brown solid. ¹H NMR (500 MHz, DMSO-d₆): δ 13.21 (br s, 1H), 8.24(s, 1H), 7.84 (s, 1H), 7.60 (t, J=6.5 Hz, 1H), 7.21-7.11 (m, 3H), 6.84(t, J=6.5 Hz, 1H), 4.34 (q, 2H), 1.81-1.76 (m, 1H), 1.32 (t, J=8.0 Hz,3H), 0.93-0.90 (m, 2H), 0.84-0.79 (m, 2H); LC-MS (ESI): m/z 474.9(M+H⁺).

Step 3: Synthesis of3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoicacid sodium salt (Compound 1-119)

To a solution of compound 4 (30 mg, 0.063 mmol) in THF:water (3:1) (4mL) was added 1M aq. NaOH solution (0.063 mL, 0.063 mmol) at RT and thenheat at 60° C. overnight. After the completion of the reaction, solventwas removed to afford Compound 1-119 sodium salt (29 mg, 100%) as anoff-white solid. LC-MS: m/z 446 (M+1).

Example 12 Synthesis of3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoicacid sodium salt (Compound 1-120)

Step 1: Synthesis of ethyl3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoate(2)

To a stirred solution of indole 1 (Example 11, Step 3; 480 mg, 1.01mmol) in DMF (10 mL) under inert atmosphere were added Cs₂CO₃ (1.32 g,4.05 mmol) and 2-bromoethan-1-ol (152 mg, 1.27 mmol) at RT and stirredfor 16 h. The mixture was diluted with water (20 mL) and extracted withEtOAc (3×20 mL). The combined organic extracts were dried (Na₂SO₄),filtered and concentrated under reduced pressure to obtain the crude.This was purified (silica gel; 55% EtOAc/hexanes) to obtain compound 2(100 mg, 19%) as a colorless syrup. ¹H NMR (400 MHz, CDCl₃): δ 7.72 (d,J=6.8 Hz, 2H), 7.62 (dt, J=8.0 Hz, 1.6 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H),7.10-7.07 (m, 1H), 6.94 (t, J=8.0 Hz, 1H), 6.78 (dt, J=8.0, 1.6 Hz, 1H),4.41 (q, 2H), 4.36-4.34 (m, 2H), 4.10 (t, J=4.8 Hz, 2H), 2.72 (br s,1H), 1.74-1.67 (m, 1H), 1.41 (t, J=7.2 Hz, 3H), 1.08-1.04 (m, 2H),0.90-0.85 (m, 2H); LC-MS: m/z 518.7 (M+H⁺).

Step 2: Synthesis of3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoicacid sodium salt (Compound 1-120)

Following the procedure of Example 11, Step 3 but using Intermediate 2in place of Intermediate 4 in Step 3, the title Compound 1-120 sodiumsalt was obtained as a white solid. LC-MS: m/z 490 (M+1).

Example 13 Synthesis of3-((1-(1-(2-(carbamoyloxy)ethyl)-1H-pyrazol-4-yl)-6-chloro-2-cyclopropyl-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoicacid sodium salt (Compound 1-121)

Step 1: Synthesis of ethyl3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-(2-phenoxycarbonyl)oxy)ethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoate (2)

To a stirred solution of indole 1 (Example 12, Step 1; 50 mg, 0.096mmol) in pyridine (2 mL) under inert atmosphere was added phenylchloroformate (18 mg, 0.11 mmol) at 0° C.; heated to 60° C. and stirredfor 1 hr. The mixture was diluted with water (20 mL), acidified with 1 Naq. HCl (5 mL) and extracted with EtOAc (2×10 mL). The combined organicextracts were washed with brine (10 mL), dried (Na₂SO₄), filtered andconcentrated under reduced pressure to obtain the crude. This waspurified (silica gel; 30% EtOAc/hexanes) to afford compound 2 (20 mg,32%) as a yellow oil. LC-MS (ESI): m/z 638.5 (M+H⁺).

Step 2: Synthesis of ethyl3-((1-(1-(2-(carbamoyloxy)ethyl)-1H-pyrazol-4-yl)-6-chloro-2-cyclopropyl-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoate(3)

To a stirred solution of compound 2 (20 mg, 0.031 mmol) in THF (3 mL)under inert atmosphere was passed ammonia gas at 0° C. for 15 min;warmed to RT and stirred for 30 min. The volatiles were removed underreduced pressure and the crude was purified by triturating withn-pentane (2×5 mL) and dried under reduced pressure to afford 3 (6 mg,35%) as a pale brown oil. ¹H NMR (500 MHz, CDCl₃): δ 7.73 (s, 1H), 7.70(s, 1H), 7.64 (t, J=8.0 Hz, 1H), 7.20 (d, J=8.5 Hz, 1H), 7.11-7.08 (m,1H), 6.95 (t, J=8.0 Hz, 1H), 6.79 (t, J=8.0 Hz, 1H), 4.65 (br s, 2H),4.54-4.47 (m, 4H), 4.42 (q, 2H), 1.74-1.70 (m, 1H), 1.43 (t, J=7.5 Hz,3H), 1.07-1.05 (m, 2H), 0.91-0.88 (m, 2H); LC-MS: m/z 561.7 (M+H⁺).

Step 3: Synthesis of3-((1-(1-(2-(carbamoyloxy)ethyl)-1H-pyrazol-4-yl)-6-chloro-2-cyclopropyl-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoicacid sodium salt (Compound 1-121)

To a solution of compound 3 (5 mg, 0.009 mmol) in THF:water (3:1) (4 mL)was added 1M aq. NaOH solution (0.009 mL, 0.009 mmol) at RT overnight.After the completion of the reaction, solvent was removed to affordCompound 1-121 sodium salt (5 mg, 100%) as an off-white solid. LC-MS:m/z 533 (M+1).

Example 14 Synthesis of3-((1-(1-(2-aminoethyl)-1H-pyrazol-4-yl)-6-chloro-2-cyclopropyl-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoicacid sodium salt (Compound 1-122)

Step 1: Synthesis of ethyl3-((1-(1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazol-4-yl)-6-chloro-2-cyclopropyl-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoate(3)

To a stirred solution of indole 1 (Example 11, Step 3; 300 mg, 0.63mmol) in DMF (5 mL) under inert atmosphere were added Cs₂CO₃ (310 mg,0.95 mmol) and tert-butyl (2-bromo ethyl)carbamate 2 (213 mg, 0.95 mmol)at RT and stirred for 16 h. The mixture was quenched with sat. aq. NH₄Cl(10 mL) and extracted with EtOAc (2×30 mL). The combined organicextracts were dried (Na₂SO₄), filtered and concentrated under reducedpressure to obtain the crude which was purified (silica gel; 30%EtOAc/hexanes) to afford compound 3 (200 mg, 51%) as a colorless syrup.¹H NMR (500 MHz, CDCl₃): δ 7.71 (s, 1H), 7.65-7.62 (m, 2H), 7.19 (d,J=8.5 Hz, 1H), 7.11-7.08 (m, 1H), 6.95 (t, J=8.0 Hz, 1H), 6.79 (t, J=6.5Hz, 1H), 4.82 (br s, 1H), 4.41 (q, 2H), 4.34 (t, J=5.0 Hz, 2H),3.65-2.04 (m, 2H), 1.72-1.68 (m, 1H), 1.43 (t, J=7.5 Hz, 3H), 1.29 (s,9H), 1.06-1.03 (m, 2H), 0.89-0.85 (m, 2H); LC-MS: 517.4 (Des-Boc)(M+H⁺).

Step 2: Synthesis of ethyl3-((1-(1-(2-aminoethyl)-1H-pyrazol-4-yl)-6-chloro-2-cyclopropyl-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoate(4)

A solution of compound 3 (200 mg, 0.32 mmol) in 4.0 M HCl in 1,4-dioxane(5 mL) under inert atmosphere was stirred at 0° C.-RT for 2 h. Thevolatiles were removed under reduced pressure. The residue was dilutedwith water (5 mL), basified with aq. NaHCO₃ (5 mL) and extracted withEtOAc (2×20 mL). The combined organic extracts were dried (Na₂SO₄),filtered and concentrated under reduced pressure to afford 4 (130 mg,81%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.24 (s, 1H),7.82 (s, 1H), 7.60 (t, J=6.8 Hz, 1H), 7.22-7.11 (m, 3H), 6.84 (t, J=6.8Hz, 1H), 4.33 (q, 2H), 4.17 (t, J=6.0 Hz, 2H), 2.98 (t, J=6.0 Hz, 2H),1.84-1.80 (m, 3H), 1.32 (t, J=7.2 Hz, 3H), 0.92-0.91 (m, 2H), 0.84-0.82(m, 2H); MS: m/z 517.6 (M+H⁺).

Step 3: Synthesis of3-((1-(1-(2-aminoethyl)-1H-pyrazol-4-yl)-6-chloro-2-cyclopropyl-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoicacid sodium salt (Compound 1-122)

Following the procedure of Example 11, Step 3 but using Intermediate 4in place of Intermediate 4 in Step 3, the title Compound 1-122 sodiumsalt was obtained as an off-white solid. LC-MS: m/z 489 (M+1).

Example 15 Synthesis of3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-(2-ureidoethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoicacid sodium salt (Compound 1-123)

Step 1: Synthesis of ethyl3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-(2-ureidoethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoate(2)

To a stirred solution of indole 1 (Example 14, Step 2; 80 mg, 0.15 mmol)in THF (5 mL) under inert atmosphere were added Et₃N (0.04 mL, 0.31mmol) and triphosgene (18.3 mg, 0.06 mmol) at 0° C., stirred for 1 h,warmed to RT and stirred for 2 h. To this solution of crude isocyanatewas passed ammonia gas at −78° C. for 10 min; warmed to 0° C. andstirred for 1 hr. The mixture was diluted with water and extracted withEtOAc (2×20 mL). The combined organic extracts were dried (Na₂SO₄),filtered and concentrated under reduced pressure to obtain the crude.This was purified by triturating with Et₂O (2×5 mL) and dried underreduced pressure to afford 2 (30 mg, 34%) as an off-white solid. ¹H NMR(400 MHz, DMSO-d₆): δ 8.19 (s, 1H), 7.82 (s, 1H), 7.60 (t, J=7.2 Hz,1H), 7.22-7.11 (m, 3H), 6.84 (t, J=7.2 Hz, 1H), 6.04-6.03 (m, 1H), 5.53(br s, 2H), 4.33 (q, 2H), 4.21 (t, J=6.0 Hz, 2H), 3.43 (t, J=6.0 Hz,2H), 1.84-1.78 (m, 1H), 1.32 (t, J=7.2 Hz, 3H), 0.92-0.91 (m, 2H),0.87-0.85 (m, 2H); MS: m/z 560.6 (M+H⁺).

Step 2: Synthesis of3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-(2-ureidoethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoicacid sodium salt (Compound 1-123)

Following the procedure of Example 13, Step 3 but using Intermediate 2in place of Intermediate 3 in Step 3, the title Compound 1-123 sodiumsalt was obtained as an off-white solid. LC-MS: m/z 532 (M+1).

Example 16 Synthesis of3-((1-(1-(3-carboxypropyl)-1H-pyrazol-4-yl)-6-chloro-2-cyclopropyl-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoicacid sodium salt (Compound 1-124)

Step 1: Synthesis of ethyl3-((1-(1-(4-(tert-butoxy)-4-oxobutyl)-1H-pyrazol-4-yl)-6-chloro-2-cyclopropyl-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoate(2)

To a stirred solution of indole 1 (Example 11, Step 3; 200 mg, 0.42mmol) in DMF (5 mL) under inert atmosphere were added Cs₂CO₃ (206 mg,0.63 mmol) and tert-butyl 4-bromobutanoate (141 mg, 0.63 mmol) at RT andstirred for 16 h. The mixture was diluted with ice cold water (20 mL)and extracted with EtOAc (3×30 mL). The combined organic extracts weredried (Na₂SO₄), filtered and concentrated under reduced pressure toobtain the crude. This was purified (silica gel chromatography; 20%EtOAc/hexanes) to afford compound 2 (180 mg, 70%) as a pale brown oil.¹H NMR (400 MHz, CDCl₃): δ 7.67 (s, 1H), 7.64 (s, 1H), 7.63-7.60 (m,1H), 7.18 (d, J=8.4 Hz, 1H), 7.10-7.06 (m, 1H), 6.93 (t, J=8.0 Hz, 1H),6.77 (t, J=7.6 Hz, 1H), 4.41 (q, 2H), 4.28 (t, J=6.8 Hz, 2H), 2.28-2.19(m, 4H), 1.74-1.66 (m, 1H), 1.46 (s, 9H), 1.41 (t, J=7.2 Hz, 3H),1.06-1.02 (m, 2H), 0.89-0.84 (m, 2H); LC-MS (ESI): m/z 618.6 (M+H⁺).

Step 2: Synthesis of4-(4-(6-chloro-2-cyclopropyl-3-((3-(ethoxycarbonyl)-2-fluorophenyl)thio)-7-fluoro-1H-indol-1-yl)-1H-pyrazol-1-yl)butanoic acid (3)

A solution of compound 2 (100 mg, 0.29 mmol) in 4.0 M HCl in 1,4-dioxane(2 mL) under inert atmosphere was stirred at 0° C.-RT for 16 h. Thevolatiles were removed in vacuo and the residue was diluted with water(5 mL), basified with aq. NaHCO₃ (5 mL) and extracted with EtOAc (2×20mL). The combined organic extracts were dried (Na₂SO₄), filtered andconcentrated under reduced pressure to obtain the crude. This waspurified by acid-base treatment to afford 3 (50 mg, 56%) as a whitesolid. ¹H NMR (500 MHz, DMSO-d₆): δ 12.75 (br s, 1H), 8.24 (s, 1H), 7.82(s, 1H), 7.59 (t, J=7.0 Hz, 1H), 7.22-7.10 (m, 3H), 6.84 (t, J=7.5 Hz,1H), 4.33 (q, 2H), 4.22 (t, J=7.0 Hz, 2H), 2.21 (t, J=7.5 Hz, 2H),2.06-2.03 (m, 2H), 1.81-1.78 (m, 1H), 1.32 (t, J=7.0 Hz, 3H), 0.89-0.88(m, 2H), 0.82-0.81 (m, 2H); MS: m/z 560.7 (M+H⁺).

Step 3: Synthesis of3-((1-(1-(3-carboxypropyl)-1H-pyrazol-4-yl)-6-chloro-2-cyclopropyl-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoicacid sodium salt (Compound 1-124)

To a solution of compound 3 (10 mg, 0.018 mmol) in THF:water (3:1) (4mL) was added 1M aq. NaOH solution (0.036 mL, 0.036 mmol) at RT and thenheated at 60° C. overnight. After the completion of the reaction,solvent was removed to afford Compound 1-124 sodium salt (10 mg, 100%)as a white solid. LC-MS: m/z 532 (M+1).

Example 17 Synthesis of3-((1-(1-(4-amino-4-oxobutyl)-1H-pyrazol-4-yl)-6-chloro-2-cyclopropyl-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoicacid sodium salt (Compound 1-125)

Step 1: Synthesis of ethyl3-((1-(1-(4-amino-4-oxobutyl)-1H-pyrazol-4-yl)-6-chloro-2-cyclopropyl-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoate(2)

To a stirred solution of indole 1 (Example 16, Step 2; 150 mg, 0.26mmol) in DMF (3 mL) under inert atmosphere were added EDCI.HCl (36 mg,0.40 mmol), HOBt (61.5 mg, 0.40 mmol), NMM (0.07 mL, 0.67 mmol) at RTand stirred for 10 min. To this, NH₄Cl (17.1 mg, 0.32 mmol) was added atRT and stirred for 16 h. The mixture was diluted with water (30 mL) andextracted with EtOAc (2×30 mL). The combined organic extracts werewashed with brine (20 mL), dried (Na₂SO₄), filtered and dried underreduced pressure to obtain the crude. This was purified (silica gel; 2%MeOH/CH₂Cl₂) to afford compound 2 (15 mg, 10%) as an off-white solid. ¹HNMR (400 MHz, DMSO-d₆): δ 8.23 (s, 1H), 7.81 (s, 1H), 7.60 (dt, J=8.0,1.6 Hz, 1H), 7.29 (br s, 1H), 7.22-7.11 (m, 3H), 6.84 (dt, J=8.0, 1.6Hz, 1H), 6.78 (br s, 1H), 4.33 (q, 2H), 4.20 (t, J=6.4 Hz, 2H),2.08-2.02 (m, 4H), 1.82-1.77 (m, 1H), 1.32 (t, J=7.2 Hz, 3H), 0.92-0.88(m, 2H), 0.86-0.80 (m, 2H); MS: m/z 559.6 (M+H⁺).

Step 2: Synthesis of3-((1-(1-(4-amino-4-oxobutyl)-1H-pyrazol-4-yl)-6-chloro-2-cyclopropyl-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoicacid sodium salt (Compound 1-125)

Following the procedure of Example 11, Step 3 but using Intermediate 2in place of Intermediate 4 in Step 3, the title Compound 1-125 sodiumsalt was obtained as a white solid. LC-MS: m/z 531 (M+1).

Example 18 Synthesis of3-((2,6-dichloro-7-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoicacid sodium salt (Compound 1-49)

Step 1: Synthesis of ethyl3-((6-chloro-7-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoate(3)

Following the procedure of Example 9, Steps 3 and 4 but usingIntermediate A in place of Intermediate B in Step 3, the title compound3 was obtained as a light brown solid. ¹H NMR (400 MHz, CDCl₃): δ 7.68(s, 1H), 7.67-7.64 (m, 2H), 7.43 (s, 1H), 7.28 (d J=8.4 Hz, 1H), 7.16(dd, J=8.4, 6.0 Hz, 1H), 7.00-6.93 (m, 2H), 4.40 (q, J=6.8 Hz, 2H), 3.99(s, 3H), 1.40 (t, J=6.8 Hz, 3H); LC-MS (ESI): m/z 448.4 (M+H⁺).

Step 2: Synthesis of ethyl3-((2,6-dichloro-7-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoate(4)

To a stirred solution of compound 3 (150 mg, 0.33 mmol) in Et₂O (10 mL)under inert atmosphere was added SO₂Cl₂ (87 mg, 0.65 mmol) at 0° C. andstirred for 1 h. The reaction mixture was quenched with water (10 mL)and extracted with EtOAc (2×20 mL). The combined organic extracts weredried over Na₂SO₄ and concentrated under reduced pressure to obtain thecrude. The crude was purified (silica gel; 15% EtOAc/n-Hexane) to afford4 (35 mg, 22%) as an off-white solid. ¹H NMR (500 MHz, CDCl₃): δ7.72-7.68 (m, 1H), 7.62 (s, 1H), 7.58 (s, 1H), 7.36 (d, J=8.5 Hz, 1H),7.24-7.19 (m, 1H), 7.08-6.79 (m, 2H), 4.42 (q, J=7.0 Hz, 2H), 4.08 (s,3H), 1.42 (t, J=7.0 Hz, 3H); LC-MS: m/z 482.4 (M⁺).

Step 3: Synthesis of3-((2,6-dichloro-7-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoicacid sodium salt (Compound 1-49)

Following the procedure of Example 11, Step 3 but using Intermediate 4in place of Intermediate 4 in Step 3, the title Compound 1-49 sodiumsalt was obtained as a tan solid. LC-MS: m/z 454 (M+1).

Example 19 Synthesis of3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoicacid sodium salt (Compound 1-126)

Step 1: Synthesis of ethyl3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoate(3)

Following the procedure of Example 9, Steps 3 and 4 but usingIntermediate F in place of Intermediate B in Step 3, the title compound3 was obtained as an off-white solid. ¹H NMR (400 MHz, CD₃OD): δ 8.23(s, 1H), 7.88 (s, 1H), 7.61 (dt, J=8.0, 1.6 Hz, 1H), 7.20 (d, J=8.4 Hz,1H), 7.15-7.11 (m, 1H), 7.02 (t, J=8.0 Hz, 1H), 6.84 (dt, J=8.4, 1.6 Hz,1H), 5.04 (q, 2H), 4.39 (q, 2H), 1.81-1.73 (m, 1H), 1.41-1.38 (m, 3H),0.98-0.90 (m, 2H), 0.88-0.84 (m, 2H); MS: m/z 556.5 (M+H⁺).

Step 2: Synthesis of3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoicacid sodium salt (Compound 1-126)

Following the procedure of Example 11, Step 3 but using Intermediate 3in place of Intermediate 4 in Step 3, the title Compound 1-126 sodiumsalt was obtained as an off-white solid. LC-MS: m/z 528 (M+1).

Example 20 Synthesis of3-((6-chloro-2-cyclopropyl-1-(1-(ethyl-d₅)-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoicacid (Compound 1-127)

Step 1: Synthesis of ethyl3-((6-chloro-2-cyclopropyl-1-(1-ethyl-d₅)-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoate(3)

Following the procedure of Example 9, Steps 3 and 4 but usingIntermediate E in place of Intermediate B in Step 3, the title compound3 was obtained as a red solid. ¹H NMR (500 MHz CDCl₃): δ 7.67-7.61 (m,3H), 7.18 (d, J=8.0 Hz, 1H), 7.09-7.07 (m, 1H), 6.94 (t, J=8.0 Hz, 1H),6.92-6.75 (m, 1H), 4.41 (q, 2H), 1.72-1.68 (m, 1H), 1.41 (t, J=7.5 Hz,3H), 1.08-1.05 (m, 2H), 0.89-0.85 (m, 2H); LC-MS (ESI): 509.5 (M+H⁺).

Step 2: Synthesis of3-((6-chloro-2-cyclopropyl-1-(1-(ethyl-d₅)-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoicacid (Compound 1-127)

To a stirred solution of indole 3 (200 mg, 0.39 mmol) in THF:MeOH:H₂O(2:2:1, 5 mL) was added LiOH.H₂O (66 mg, 1.57 mmol) at RT and stirredfor 8 h. The volatiles were removed in vacuo. The residue was dilutedwith water (5 mL), acidified with 2 M aq. HCl (5 mL); the obtained solidwas filtered, washed with water (25 mL), triturated with n-pentane (2×5mL) and dried under reduced pressure to afford the title Compound 1-127(110 mg, 59%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 13.49(br s, 1H), 8.22 (s, 1H), 7.73 (s, 1H), 7.51 (t, J=6.8 Hz, 1H),7.19-7.13 (m, 2H), 7.04 (t, J=8.0 Hz, 1H), 6.74 (t, J=7.2 Hz, 1H),1.80-1.73 (m, 1H), 0.91-0.90 (m, 2H), 0.82-0.80 (m, 2H); MS (ESI): m/z480.8 (M+H⁺).

Example 21 Synthesis of3-((2,6-dichloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoicacid sodium salt (Compound 1-31)

Step 1: Synthesis of ethyl3-((6-chloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoate(3)

Following the procedure of Example 9, Steps 3 and 4 but using indole 1(Example 4, Step 1) in place of indole 3 in Step 3, the title compound 3was obtained as a light brown solid. ¹H NMR (500 MHz, CDCl₃): δ7.69-7.64 (m, 3H), 7.44 (s, 1H), 7.27 (t, J=8.0 Hz, 1H), 7.16 (dd,J=8.5, 6.0 Hz, 1H), 7.01-6.94 (m, 2H), 4.40 (q, J=7.5 Hz, 2H), 4.26 (q,J=8.0 Hz, 2H), 1.57 (t, J=8.0 Hz, 3H), 1.57 (t, J=7.5 Hz, 3H); LC-MS(ESI): m/z 462.5 (M+H⁺).

Step 2: Synthesis of ethyl3-((2,6-dichloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoate(4)

To a solution of compound 3 (100 mg, 0.21 mmol) in CH₂Cl₂ (3 mL) underinert atmosphere was added NCS (58 mg, 0.43 mmol) at RT and stirred for16 h. The reaction mixture was diluted with water (10 mL) and extractedwith CH₂Cl₂ (2×15 mL). The combined organic extracts were dried overNa₂SO₄ and concentrated under reduced pressure to obtain the crude. Thecrude was purified (silica gel; 14-17% EtOAc/Hexanes) to afford 5 (35mg, 33%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃): δ 7.71-7.66 (m,3H), 7.30 (d, J=7.6 Hz, 1H), 7.19 (dd, J=8.8, 6.4 Hz, 1H), 7.04-6.97 (m,2H), 4.40 (q, J=7.2 Hz, 2H), 4.27 (q, J=7.6 Hz, 2H), 1.58 (t, J=7.6 Hz,3H), 1.49 (t, J=7.2 Hz, 3H); LC-MS (ESI): m/z 496.7 (M+H⁺).

Step 3: Synthesis of3-((2,6-dichloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoicacid (Compound 1-31)

Following the procedure of Example 11, Step 3 but using Intermediate 4in place of Intermediate 4 in Step 3, the title Compound 1-31 sodiumsalt was obtained as an off-white solid. LC-MS: m/z 468 (M+1).

Example 22 Synthesis of3-((2,6-dichloro-7-fluoro-1-(pyridin-3-yl)-1H-indol-3-yl)thio)-2-fluorobenzoicacid sodium salt (Compound 2-1)

Step 1: Synthesis of 6-chloro-7-fluoro-1-(pyridin-3-yl)-1H-indole (2)

To a stirred solution of indole 1 (Example 4, Step 1; 2.0 g, 11.8 mmol)in toluene (50 mL) were added 3-bromopyridine (2.9 g, 17.7 mmol),N,N′-dimethylethylenediamine (418 mg, 4.73 mmol), K₃PO₄ (6.3 g, 29.5mmol), CuI (225 mg, 1.18 mmol) at RT under inert atmosphere. The mixturewas purged with argon for 15 min and heated to 140° C. in a sealed tubefor 16 h. The reaction mixture was cooled to RT, added n-hexane (20 mL),stirred for 5 minutes and then filtered. The filtrate was diluted withwater (20 mL) and extracted with EtOAc (2×50 mL). The combined organicextracts were washed with water and brine solution, dried over Na₂SO₄,filtered and concentrated under reduced pressure to obtain the crude.The crude was purified (silica gel; 10% EtOAc/Hexanes) to affordcompound 2 (2.0 g, 69%) as light brown solid. ¹H NMR (500 MHz, DMSO-d₆):δ 8.84 (s, 1H), 8.66 (d, J=5.0 Hz, 1H), 8.06-8.02 (m, 1H), 7.74-7.72 (m,1H), 7.64-7.58 (m, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.28-7.24 (m, 1H), 6.82(m, 1H).

Step 2: Synthesis of ethyl3-((6-chloro-7-fluoro-1-(pyridin-3-yl)-1H-indol-3-yl)thio)-2-fluorobenzoate(3)

To a stirred solution of Intermediate A (243 mg, 1.21 mmol) in1,2-dichloroethane (8 mL) under inert atmosphere was added NCS (163 mg,1.21 mmol) at RT and stirred for 1 h. To this, compound 2 (200 mg, 0.81mmol) in 1,2-dichloroethane (2 mL) and NaHCO₃ (204 mg, 2.45 mmol) wereadded at RT. After 24 h stirring at RT, the reaction mixture was dilutedwith water (15 mL) and extracted with EtOAc (2×30 mL). The combinedorganic extracts were washed with water (30 mL) and brine (30 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to obtainthe crude. The crude was purified (silica gel; 10% EtOAc/Hexanes) toafford compound 3 (50 mg, 9%) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆): δ 8.91 (s, 1H), 8.70 (d, J=5.0 Hz, 1H), 8.30 (s, 1H),8.18-8.15 (m, 1H), 7.66-7.762 (m, 2H), 7.36-7.34 (m, 2H), 7.17-7.13 (m,2H), 4.34 (q, J=7.5 Hz, 2H), 1.32 (t, J=7.5 Hz, 3H).

Step 3: Synthesis of ethyl3-((2,6-dichloro-7-fluoro-1-(pyridin-3-yl)-1H-indol-3-yl)thio)-2-fluorobenzoate(4)

To a stirred solution of compound 3 (50 mg, 0.11 mmol) in Et₂O (10 mL)under inert atmosphere was added SO₂Cl₂ (18 mg, 0.13 mmol) slowly at 0°C. and stirred for 1 h. After completion of the reaction by TLC, thereaction mixture was quenched with water (10 mL) and extracted withEtOAc (2×20 mL). The combined organic extracts were washed with water,brine solution, dried over Na₂SO₄ and concentrated under reducedpressure to obtain the crude. The crude was purified by preparative HPLCto afford 4 (17 mg, 32%) as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆): δ 8.93 (d, J=2.4 Hz, 1H), 8.80 (dd, J=4.8, 1.6 Hz, 1H),8.23-8.21 (m, 1H), 7.71-7.66 (m, 2H), 7.39-7.38 (m, 2H), 7.20-7.18 (m,2H), 4.34 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H); LC-MS: m/z 479.4(M⁺).

Step 4: Synthesis of3-((2,6-dichloro-7-fluoro-1-(pyridin-3-yl)-1H-indol-3-yl)thio)-2-fluorobenzoicacid sodium salt (Compound 2-1)

To a solution of compound 4 (16 mg, 0.033 mmol) in THF:water (3:1) (4mL) was added 1M aq. NaOH solution (0.033 mL, 0.033 mmol) at RT and thenheated at 60° C. for 3 hours. After the completion of the reaction,solvent was removed to afford Compound 2-1 sodium salt (16 mg, 100%) asan off-white solid. LC-MS: m/z 451 (M+1).

Alternate Route for Compound 4 Preparation

Step 1: Synthesis of ethyl3-((6-chloro-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoate (2)

To a stirred solution of Intermediate A (1.18 g, 5.91 mmol) in CH₂Cl₂(30 mL) under inert atmosphere was added NCS (792 mg, 5.91 mmol) at RTand stirred for 1 h. To this, indole 1 (Example 4, Step 1; 1.0 g, 5.91mmol) in CH₂Cl₂ (20 mL) was added at RT and stirred for 4 h. Aftercompletion of the reaction by TLC, the reaction mixture was diluted withwater (40 mL) and extracted with CH₂Cl₂ (2×60 mL). The combined organicextracts were washed with water (50 mL) and brine (50 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to obtain thecrude. The crude was purified (silica gel; 10% EtOAc/Hexanes) to affordcompound 2 (1.2 g, 55%) as a light brown solid. ¹H NMR (500 MHz,DMSO-d₆): δ 12.60 (br s, 1H), 8.00 (d, J=4.0 Hz, 1H), 7.61-7.57 (m, 1H),7.24-7.17 (m, 2H), 7.09 (t, J=8.0 Hz, 1H), 6.90-6.86 (m, 1H), 4.34 (q,J=7.5 Hz, 2H), 1.32 (t, J=7.5 Hz, 3H); MS: m/z 368.6 (M+H⁺).

Synthesis of ethyl3-((6-chloro-7-fluoro-1-(pyridin-3-yl)-1H-indol-3-yl)thio)-2-fluorobenzoate

To a stirred solution of compound 2 (200 mg, 0.54 mmol) in toluene (5mL) were added 3-bromopyridine (131 mg, 0.81 mmol),trans-1,2-diaminocyclohexane (24.8 mg, 0.21 mmol), K₃PO₄ (288 mg, 1.35mmol), Cu(I)I (10.3 mg, 0.05 mmol) at RT under inert atmosphere. Themixture was purged with argon for 15 min and heated to 140° C. in asealed tube for 16 h. The reaction mixture was cooled to RT, addedn-hexane (6 mL), stirred for 5 minutes and then filtered. The filtratewas diluted with water (20 mL) and extracted with EtOAc (2×50 mL). Thecombined organic extracts were washed with water and brine solution,dried over Na₂SO₄, filtered and concentrated under reduced pressure toobtain the crude. The crude was purified (silica gel; 10-12%EtOAc/Hexanes) to afford compound 3 (130 mg, 54%) as an off-white solid.

Example 23 Synthesis of3-((2-bromo-6-chloro-7-fluoro-1-(pyridin-3-yl)-1H-indol-3-yl)thio)-2-fluorobenzoicacid (Compound 2-2)

Step 1: Synthesis of ethyl3-((2-bromo-6-chloro-7-fluoro-1-(pyridin-3-yl)-1H-indol-3-yl)thio)-2-fluorobenzoate(2)

To a stirred solution of indole 1 (Example 22, Step 2; 60 mg, 0.13 mmol)in CH₂Cl₂ (5 mL) under inert atmosphere was added NBS (60 mg, 0.33 mmol)at RT and stirred for 16 h. The mixture was diluted with water (10 mL)and extracted with CH₂Cl₂ (2×25 mL). The combined organic extracts werewashed with brine (10 mL), dried (Na₂SO₄), filtered and concentratedunder reduced pressure to obtain the crude. This was purified (silicagel; 10% EtOAc/hexanes) to afford compound 2 (35 mg, 50%) as a palebrown solid. ¹H NMR (500 MHz, DMSO-d₆): δ 8.91 (s, 1H), 8.81-8.80 (m,1H), 8.20 (d, J=8.5 Hz, 1H), 7.70-7.66 (m, 2H), 7.40-7.37 (m, 2H), 7.18(t, J=8.0 Hz, 1H), 7.16-7.13 (m, 1H), 4.33 (q, 2H), 1.32 (t, J=7.5 Hz,3H); MS: m/z 525.3 (M⁺+2).

Step 2: Synthesis of3-((2-bromo-6-chloro-7-fluoro-1-(pyridin-3-yl)-1H-indol-3-yl)thio)-2-fluorobenzoicacid (Compound 2-2)

To a stirred solution of compound 2 (35 mg, 0.06 mmol) in THF: H₂O (1:1,4 mL) was added LiOH.H₂O (11.2 mg, 0.26 mmol) at RT and stirred for 5 h.The volatiles were removed under reduced pressure and the residue wasdiluted with water (5 mL), acidified with citric acid and extracted withEtOAc (2×25 mL). The combined organic extracts were washed with brine(10 mL), dried (Na₂SO₄), filtered and concentrated under reducedpressure to obtain the crude. This was triturated with n-pentane (2×5mL) and dried in vacuo to afford the title Compound 2-2 (25 mg, 76%) asa pale brown solid. ¹H NMR (500 MHz, DMSO-d₆): δ13.41 (br s, 1H), 8.93(s, 1H), 8.81-8.80 (m, 1H), 8.20 (d, J=7.5 Hz, 1H), 7.70-7.64 (m, 2H),7.40-7.35 (m, 2H), 7.17-7.11 (m, 2H); LC-MS (ESI): m/z 497.3 (M⁺+2).

Example 24 Synthesis of3-((6-chloro-2-cyclopropyl-7-fluoro-1-(pyridin-3-yl)-1H-indol-3-yl)thio)-2-fluorobenzoicacid sodium salt (Compound 2-3)

Step 1: Synthesis of ethyl3-((6-chloro-2-cyclopropyl-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoate(3)

To a stirred solution of Intermediate A (190 mg, 0.95 mmol) in CH₂Cl₂(10 mL) under inert atmosphere was added NCS (128 mg, 0.95 mmol) at RTand stirred for 1 h. To this, indole 1 (Example 9, Step 2; 200 mg, 0.95mmol) in CH₂Cl₂ (5 mL) was added at RT and stirred for 12 h. The mixturewas diluted with water (50 mL) and extracted with CH₂Cl₂ (3×50 mL). Thecombined organic extracts were washed with brine (100 mL), dried(Na₂SO₄), filtered and concentrated under reduced pressure to obtain thecrude. This was purified (silica gel chromatography; 5-10%EtOAc/hexanes) to obtain compound 2 (300 mg, 77%) as a pale pink solid.¹H NMR (400 MHz, DMSO-d₆): δ 11.91 (s, 1H), 7.89-7.84 (m, 1H), 7.57 (t,J=8.0 Hz, 1H), 7.14-7.07 (m, 2H), 6.78 (t, J=8.0 Hz, 1H), 4.35-4.29 (m,2H), 2.32-2.25 (m, 1H), 1.33-1.28 (m, 3H), 1.15-1.10 (m, 2H), 1.08-1.03(m, 2H); LC-MS (ESI): m/z 406.3 (M −H⁺).

Step 2: Synthesis of ethyl3-((6-chloro-2-cyclopropyl-7-fluoro-1-(pyridin-3-yl)-1H-indol-3-yl)thio)-2-fluorobenzoate(3)

To a stirred solution of compound 2 (100 mg, 0.24 mmol) in toluene (5mL) were added 3-bromopyridine (59.3 mg, 0.36 mmol),trans-1,2-diaminocyclohexane (11.2 mg, 0.098 mmol), K₃PO₄ (130 mg, 0.65mmol), CuI (4.6 mg, 0.024 mmol) at RT under argon in a sealed tube. Thesolution was purged with argon; heated to 140° C. and stirred for 40 h.The mixture was cooled to RT, added n-hexane (6 mL), stirred for 5minutes and then filtered. The filtrate was diluted with water (20 mL)and extracted with EtOAc (2×50 mL). The combined organic extracts werewashed with water and brine solution, dried (Na₂SO₄), filtered andconcentrated under reduced pressure to obtain the crude. This waspurified (silica gel; 5-10% EtOAc/hexanes) to afford compound 3 (10 mg,8.4%) as a pale brown solid. ¹H NMR (400 MHz, CDCl₃): δ 8.77 (br s, 2H),7.81 (d, J=8.0 Hz, 1H), 7.68-7.62 (m, 1H), 7.53-7.50 (m, 1H), 7.25-7.23(m, 1H), 7.17-7.11 (m, 1H), 6.96 (t, J=7.6 Hz, 1H), 6.82 (dt, J=8.4, 1.6Hz, 1H), 4.40 (q, 2H), 1.65-1.60 (m, 1H), 1.41 (t, J=7.2 Hz, 3H),0.91-0.82 (m, 4H); LC-MS (ESI): m/z 485.5 (M+H⁺).

Step 3: Synthesis of3-((6-chloro-2-cyclopropyl-7-fluoro-1-(pyridin-3-yl)-1H-indol-3-yl)thio)-2-fluorobenzoicacid sodium salt (Compound 2-3)

Following the procedure of Example 11, Step 3 but using Intermediate 3in place of Intermediate 4 in Step 3, the title Compound 2-3 sodium saltwas obtained as an off-white solid. LC-MS: m/z 457 (M+1).

Example 25 Synthesis of3-((1-(1-(6-aminoethyl)-1H-pyrazol-4-yl)-6-chloro-2-cyclopropyl-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoicacid sodium salt (Compound 1-128)

Step 1: Synthesis of tert-butyl (6-hydroxyhexyl)carbamate (2)

To a stirred solution of 6-aminohexan-1-ol (1 g, 8.55 mmol) in THF (20mL) was added Boc₂O (1.86 g, 8.55 mmol) at RT under inert atmosphere andstirred for 6 h. The mixture was diluted with water (50 mL) andextracted with EtOAc (3×60 mL). The combined organic extracts were driedover Na₂SO₄, filtered and concentrated under reduced pressure to obtainthe crude. The crude was purified (silica gel chromatography; 30%EtOAc/hexanes) to afford compound 2 (1 g, 54%) as colorless syrup. ¹HNMR (400 MHz, CDCl₃): δ 4.51 (br s, 1H), 3.63 (t, J=6.4 Hz, 2H),3.14-3.09 (m, 2H), 1.60-1.53 (m, 2H), 1.52-1.48 (m, 2H), 1.47 (s, 9H),1.41-1.30 (m, 4H); LC-MS (ESI): m/z 118.1 (M⁺−Boc).

Step 2: Synthesis of tert-butyl (6-bromohexyl)carbamate (3)

To a stirred solution of compound 2 (1 g, 4.61 mmol) in toluene (30 mL)were added Ph₃P (1.81 g, 6.91 mmol) and CBr₄ (2.29 g, 6.91 mmol) at RTunder inert atmosphere and stirred for 3 h. The mixture was diluted withwater (50 mL) and extracted with EtOAc (3×60 mL). The combined organicextracts were dried over Na₂SO₄, filtered and concentrated in vacuo toobtain the crude. The crude was purified (silica gel; 20% EtOAc/hexanes)to afford compound 3 (1 g, 78%) as colorless oil. ¹H NMR (400 MHz,CDCl₃): δ 4.51 (br s, 1H), 3.40 (t, J=6.8 Hz, 2H), 3.13-3.08 (m, 2H),1.89-1.82 (m, 2H), 1.52-1.42 (m, 13H), 1.37-1.31 (m, 2H).

Step 3: Synthesis of3-((1-(1-(6-aminohexyl)-1H-pyrazol-4-yl)-6-chloro-2-cyclopropyl-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoicacid sodium salt (Compound 1-128)

Following the procedure of Example 14 but using compound 3 in place oftert-butyl (2-bromo ethyl)carbamate, the title Compound 1-128 sodiumsalt was obtained as an off-white solid. LC-MS: m/z 545 (M+1).

Example 26 Synthesis of3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-(hex-5-yn-1-yl)-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoicacid sodium salt (Compound 1-129)

Following the procedure of Example 12 but using 6-bromohex-1-yne inplace of 2-bromoethan-1-ol in Step 1, the title Compound 1-129 sodiumsalt was obtained as a white solid. LC-MS: m/z 526 (M+1).

Example 27 Synthesis of3-((1-(1-(3-hydroxy-2,2-dimethylpropyl)-1H-pyrazol-4-yl)-6-chloro-2-cyclopropyl-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoicacid sodium salt (Compound 1-130)

Following the procedure of Example 12 but using3-bromo-2,2-dimethyl-propan-1-ol in place of 2-bromoethan-1-ol in Step1, the title Compound 1-130 sodium salt was obtained as a white solid.LC-MS: m/z 481 (M+1).

Example 28 Synthesis of3-((6-chloro-2-cyclopropyl-1-(1-(6-(3-(3′,6′-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9′-xanthen]-5-yl)ureido)hexyl)-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoicacid sodium salt (Compound 1-131)

To a stirred solution of amine 1 (Example 25; 11.1 mg, 0.020 mmol) inCH₂Cl₂ (2 mL) under inert atmosphere was added fluorescein isothiocyante(7.6 mg, 0.020 mmol), followed by DIEA (3.4 μL, 0.020 mmol). The mixturewas then stirred at room temperature under N₂ for overnight. Aftercompletion of the reaction, the mixture was evaporated to dryness. Thecrude was then purified by Prep HPLC to afford 3 mg of the titleCompound 1-131 as an orange solid. LC-MS: m/z 934 (M+1).

Example 29 Synthesis of2-(3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-ethyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorophenyl)aceticacid (compound 2-7)

To a stirred solution of3-((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoicacid compound 1-34 (Example 9; 30 mg, 0.058 mmol) in toluene (2.0 mL)under inert atmosphere was added thionyl chloride (0.22 mL, 3.0 mmol)and the mixture was heated at 85° C. for 2 h. The volatiles were removedunder reduced pressure and the residue was resuspended in toluene (2.0mL) and (trimethylsilyl)diazomethane solution (2.0 M in hexanes, 0.88mL, 0.88 mmol). After evolution of gas, t-butylalcohol (2.0 mL) wasadded and the mixture was heated for 0.5 hr at 50° C. The residue waspurified by silica gel chromatography (0-20% Hx/EtOAC). Afterevaporation of the fractions, the residue was dissolved in 4.0 M HCl in1,4-dioxane (0.5 mL) and the solution was stirred at RT for 2 hr. Thesolvent was removed and the residue was purified by HPLC to give thetarget compound as a clear film. MS (ESI): m/z 488.0 (M+H⁺).

Example 30 Parenteral Pharmaceutical Composition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection (subcutaneous, intravenous), 1-100 mg of awater-soluble salt of a compound described herein, or a pharmaceuticallyacceptable salt or solvate thereof, is dissolved in sterile water andthen mixed with 10 mL of 0.9% sterile saline. A suitable buffer isoptionally added as well as optional acid or base to adjust the pH. Themixture is incorporated into a dosage unit form suitable foradministration by injection.

Example 31 Oral Solution

To prepare a pharmaceutical composition for oral delivery, a sufficientamount of a compound described herein, or a pharmaceutically acceptablesalt thereof, is added to water (with optional solubilizer(s), optionalbuffer(s) and taste masking excipients) to provide a 20 mg/mL solution.

Example 32 Oral Tablet

A tablet is prepared by mixing 20-50% by weight of a compound describedherein, or a pharmaceutically acceptable salt thereof, 20-50% by weightof microcrystalline cellulose, 1-10% by weight of low-substitutedhydroxypropyl cellulose, and 1-10% by weight of magnesium stearate orother appropriate excipients. Tablets are prepared by directcompression. The total weight of the compressed tablets is maintained at100-500 mg.

Example 33 Oral Capsule

To prepare a pharmaceutical composition for oral delivery, 10-500 mg ofa compound described herein, or a pharmaceutically acceptable saltthereof, is mixed with starch or other suitable powder blend. Themixture is incorporated into an oral dosage unit such as a hard gelatincapsule, which is suitable for oral administration.

In another embodiment, 10-500 mg of a compound described herein, or apharmaceutically acceptable salt thereof, is placed into Size 4 capsule,or size 1 capsule (hypromellose or hard gelatin) and the capsule isclosed.

Example 34 Topical Gel Composition

To prepare a pharmaceutical topical gel composition, a compounddescribed herein, or a pharmaceutically acceptable salt thereof, ismixed with hydroxypropyl celluose, propylene glycol, isopropyl myristateand purified alcohol USP. The resulting gel mixture is then incorporatedinto containers, such as tubes, which are suitable for topicaladministration.

Example 35 Human Autotaxin Assay

ATX activity is assayed in concentrated conditioned media from Hep3Bhuman hepatocellular carcinoma cells by measuring the amount of cholinereleased from the substrate, lysophosphatidylcholine (LPC) as it iscleaved to LPA. Conditioned media is collected from confluent Hep3Bcells and concentrated 20-fold using Centriprep-30 filter devices(Millipore). To assay for autotaxin inhibition, 10-20 μL of theconcentrated conditioned media is incubated with 2.5 μL of a testcompound in DMSO and 72.5-82.5 μL lyso-PLD buffer (100 mM Tris pH 9, 500mM NaCl, 5 mM MgCl₂, 5 mM CaCl₂, 0.05% Triton X-100 in the presence orabsence of 0.2% fatty-acid-free human serum albumin) for 15 min at 37°C. After the 15 min incubation, 5 ul of 2 mM LPC (14:0; Avanti PolarLipids Cat#855575C) diluted in lyso-PLD buffer is added for a finalconcentration of 100 uM and the incubation continues for 1.5-3 hours at37° C. 100 μl of a color mix containing 4.5 mM 4-aminoantipyrine, 2.7 mMN-ethyl-N-(2-hydroxy-3-sulfopropyl)-m-toluidine, 21 units/ml horseradishperoxidase and 3 units/ml choline oxidase in 50 mM Tris, pH 8, 4.5 mMMgCl₂ is added and the incubation continued for 15 minutes at roomtemperature before reading the absorbance at 555 nm.

Illustrative biological activity of representative compounds in thehuman autotaxin assay described herein is presented in the followingtable:

Compound number IC₅₀ (μM) 1-1 A 1-2 A 1-3 A 1-4 A 1-7 A  1-10 A  1-13 A 1-16 A  1-31 A  1-34 A  1-49 A  1-92 A  1-119 A  1-120 A  1-121 A 1-122 A  1-123 A  1-124 A  1-125 A  1-126 A  1-127 A  1-127 A  1-128 A 1-129 A  1-130 A  1-131 A 2-1 A 2-2 A 2-3 A 2-7 A

-   -   A is ≦0.5 μM; B is >0.5 μM but ≦3 μM; C >3 μM.

Example 36 Human Whole Blood Autotaxin Assay

Inhibition of ATX activity in human whole blood is assayed by measuringthe concentration of 20:4 LPA in plasma after a prolonged incubation at37° C. Blood is drawn from consenting human volunteers into heparinvacutainer tubes and 200 μl aliquots are added to 2 μl test compound inDMSO or DMSO alone. Several of the vehicle tubes are centrifugedimmediately at 800×g for 10 minutes at 4° C. and the plasma removed forprocessing to determine the baseline concentration of 20:4 LPA. Theremaining blood samples containing vehicle or test compound areincubated at 37° C. for 4 hours before centrifuging at 800×g for 10minutes at 4° C. to obtain plasma. Plasma is processed for LCMS asfollows: 40 μl plasma is removed and 5 volumes of methanol containing125 ng/ml 17:0 LPA as an internal standard are added and the mixtureincubated at −20° C. for 10 min before centrifuging at 4000×g for 10minutes at 4° C. 150 μl of the supernatant is transferred to a 96-wellplate and diluted with 100 μl of an organic solution (90:10:0.1 ofwater/acetonitrile/ammonium hydroxide) for analysis of 20:4 LPAconcentrations by LCMS. LPA 20:4 and the internal standard (LPA 17:0)were analyzed on a quadrupole mass spectrometer (ABI Sciex 4000QTrap) inthe negative ion mode (ESI) by multiple reaction monitoring (MRM). Themobile phases contain 0.1% ammonium hydroxide in 90% water/10%acetonitrile (solvent A) and 0.1% ammonium hydroxide in 90%acetonitrile/10% water (solvent B). The flow rate was maintained at 0.8mL/min and the total run time was 3 min. Analytes were separated using alinear gradient as follows: 1) mobile phase was held for 0.5 min at 10%B; 2) B was increased from 10% to 90% over the next 1 min; 3) B was heldconstant for 0.5 min at 90%; and 4) B was returned to the initialgradient conditions.

The examples and embodiments described herein are for illustrativepurposes only and various modifications or changes suggested to personsskilled in the art are to be included within the spirit and purview ofthis application and scope of the appended claims.

1-34. (canceled)
 35. A method for the treatment or prevention offibrosis in a mammal comprising administering a therapeuticallyeffective amount of a compound that has the following structure, or apharmaceutically acceptable salt, or solvate thereof, to the mammal inneed thereof:

wherein, W is CF or N; R^(A) is H, halogen, —CN, —OH, —OR⁹, —SR⁹,C₁-C₆alkyl, or C₁-C₆fluoroalkyl; R⁹ is C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆deuteroalkyl, or C₃-C₆cycloalkyl; R^(B) is H, C₁-C₆alkyl,C₁-C₆fluoroalkyl, or C₁-C₆deuteroalkyl; L¹ is absent, C₁-C₆alkylene, orC₃-C₆cycloalkylene; R² is halogen, —CN, —OH, C₁-C₄alkyl,C₁-C₄fluoroalkyl, C₁-C₄deuteroalkyl, C₁-C₄alkoxy, or C₁-C₄fluoroalkoxy;and R³ is halogen, —CN, —OH, C₁-C₄alkyl, C₁-C₄fluoroalkyl,C₁-C₄deuteroalkyl, C₁-C₄alkoxy, or C₁-C₄fluoroalkoxy.
 36. The method ofclaim 35, further comprising administering a second therapeutic agent tothe mammal.
 37. The method of claim 35, wherein: the fibrosis is lungfibrosis, liver fibrosis, heart fibrosis, kidney fibrosis, skinfibrosis, or fibrosis of the gastrointestinal tract.
 38. The method ofclaim 35, wherein: R^(A) is H, F, Cl, Br, I, —CN, —OH, —OCH₃, —OCH₂CH₃,—OCF₃, —OCH₂CF₃, —CH₃, —CH₂CH₃, —CF₃, or —CD₃.
 39. The method of claim35, wherein: R^(B) is C₁-C₆alkyl.
 40. The method of claim 35, wherein:R² is F, Cl, Br, I, —CN, —OH, —CH₃, —CF₃, —CD₃, —OCH₃, —OCH₂CH₃, —OCF₃,or —OCH₂CF₃; and R³ is F, Cl, Br, I, —CN, —OH, —CH₃, —CF₃, —CD₃, —OCH₃,—OCH₂CH₃, —OCF₃, or —OCH₂CF₃.
 41. The method of claim 35, wherein: R² isCl; and R³ is F, or Cl.
 42. The method of claim 35, wherein: L¹ isabsent, —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, or cyclopropyl-1,1-diyl.
 43. Themethod of claim 35, wherein: L¹ is absent.
 44. The method of claim 35,wherein the compound is:3-((2,6-dichloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoicacid;3-((2,6-dichloro-7-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoicacid; or3-((2,6-dichloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoicacid; or a pharmaceutically acceptable salt, or solvate thereof.
 45. Themethod of claim 35, wherein the compound is:3-((2,6-dichloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoicacid; or a pharmaceutically acceptable salt, or solvate thereof.
 46. Themethod of claim 35, wherein the compound is:3-((2,6-dichloro-7-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoicacid; or a pharmaceutically acceptable salt, or solvate thereof.
 47. Themethod of claim 35, wherein the compound is:3-((2,6-dichloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoicacid; or a pharmaceutically acceptable salt, or solvate thereof.
 48. Themethod of claim 35, wherein the compound is administered to the mammalby oral administration, by intravenous administration, by subcutaneousadministration, by inhalation, by nasal administration, by dermaladministration, or by ophthalmic administration.
 49. The method of claim35, wherein the compound is administered to the mammal in apharmaceutical composition that is in the form of a tablet, a pill, acapsule, a liquid, a suspension, a gel, a dispersion, a solution, anemulsion, an ointment, or a lotion.